2010 - University of Auckland

Antenatal Magnesium SulphatePrior to Preterm Birth for Neuroprotection

of the Fetus, Infant and Child

Antenatal M

agnesium Sulphate Prior to Preterm

Birth for Neuroprotection of the Fetus, Infant and Child

Prepared by the

Antenatal Magnesium Sulphate

For Neuroprotection

Guideline Development Panel

2010

Nati onal Clinical Practi ce Guidelines

©AustralianResearchCentreforHealthofWomenandBabies,TheUniversityofAdelaide2010

Printeddocument

Thisworkiscopyright.ApartfromanyuseaspermittedundertheCopyrightAct1968,nopartmay

bereproducedbyanyprocesswithoutpriorwrittenpermissionfromtheAustralianResearchCentre

forHealthofWomenandBabies,TheUniversityofAdelaide.Requestsandinquiriesconcerning

reproductionandrightsshouldbeaddressedtoARCH,DisciplineofObstetricsandGynaecology,

Women’sandChildren’sHospitalAdelaide,72KingWilliamRoad,NorthAdelaide,SA,5006.

ISBNPrint:978‐0‐86396‐720‐7

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emailed,reserved.Requestsandinquiriesconcerningreproductionandrightsshouldbeto [email protected]

ISBNPrint:978‐0‐86396‐720‐7

Forfurtherinformation:

Web:www.auckland.ac.nz/en/liggins/our-research/research-themes/healthy-mothers-healthy-babies/research-synthesis.html

Email:[email protected]

Suggestedcitation:

TheAntenatalMagnesiumSulphateforNeuroprotectionGuidelineDevelopmentPanel.Antenatal

magnesiumsulphatepriortopretermbirthforneuroprotectionofthefetus,infantandchild:

Nationalclinicalpracticeguidelines.Adelaide:TheUniversityofAdelaide,2010.

Disclaimer

Theseguidelinesareageneralguidetoappropriatepracticetobeusedsubjecttothehealth

practitioner’sclinicaljudgementandtheindividualwoman’spreference.Thedocumentisdesigned

togiveinformationtoassistclinicaldecision‐makingandisbasedonthebestavailableevidenceat

thetimeofrelease.

PublicationApproval

TheseguidelineswereapprovedbytheChiefExecutiveOfficeroftheNationalHealthandMedical

ResearchCouncil(NHMRC)on17November2010underSection14AoftheNationalHealthand

MedicalResearchCouncilAct1992.InapprovingtheseguidelinestheNHMRCconsidersthatthey

meettheNHMRCstandardforclinicalpracticeguidelinesinthattheyarebasedonthesystematic

identificationandsynthesisofthebestavailablescientificevidenceandmakeclear

recommendationsforhealthprofessionalspractisinginanAustralianhealthcaresetting.The

NHMRCexpectsthatallguidelineswillbereviewednolessthanonceeveryfiveyears.

ThispublicationreflectstheviewsoftheauthorsandnotnecessarilytheviewsoftheAustralianGovernment.

©AustralianResearchCentreforHealthofWomenandBabies,TheUniversityofAdelaide2010

Printeddocument

Thisworkiscopyright.ApartfromanyuseaspermittedundertheCopyrightAct1968,nopartmay

bereproducedbyanyprocesswithoutpriorwrittenpermissionfromtheAustralianResearchCentre

forHealthofWomenandBabies,TheUniversityofAdelaide.Requestsandinquiriesconcerning

reproductionandrightsshouldbeaddressedtoARCH,DisciplineofObstetricsandGynaecology,

Women’sandChildren’sHospitalAdelaide,72KingWilliamRoad,NorthAdelaide,SA,5006.

ISBNPrint:978‐0‐86396‐720‐7

Electronicdocument

Thisworkiscopyright.Youmaydownload,display,printandreproducethismaterialinunaltered

formonly(retainingthisnotice)foryourpersonal,non‐commercialuseorusewithinyour

organisation.ApartfromanyuseaspermittedundertheCopyrightAct1968,allotherrightsare

reserved.RequestsandinquiriesconcerningreproductionandrightsshouldbeaddressedtoARCH,

DisciplineofObstetricsandGynaecology,Women’sandChildren’sHospitalAdelaide,72King

WilliamRoad,NorthAdelaide,SA,5006.

ISBNPrint:978‐0‐86396‐720‐7

Forfurtherinformation:

Web:www.adelaide.edu.au/arch

Email:[email protected]

Suggestedcitation:

TheAntenatalMagnesiumSulphateforNeuroprotectionGuidelineDevelopmentPanel.Antenatal

magnesiumsulphatepriortopretermbirthforneuroprotectionofthefetus,infantandchild:

Nationalclinicalpracticeguidelines.Adelaide:TheUniversityofAdelaide,2010.

Disclaimer

Theseguidelinesareageneralguidetoappropriatepracticetobeusedsubjecttothehealth

practitioner’sclinicaljudgementandtheindividualwoman’spreference.Thedocumentisdesigned

togiveinformationtoassistclinicaldecision‐makingandisbasedonthebestavailableevidenceat

thetimeofrelease.

PublicationApproval

TheseguidelineswereapprovedbytheChiefExecutiveOfficeroftheNationalHealthandMedical

ResearchCouncil(NHMRC)on17November2010underSection14AoftheNationalHealthand

MedicalResearchCouncilAct1992.InapprovingtheseguidelinestheNHMRCconsidersthatthey

meettheNHMRCstandardforclinicalpracticeguidelinesinthattheyarebasedonthesystematic

identificationandsynthesisofthebestavailablescientificevidenceandmakeclear

recommendationsforhealthprofessionalspractisinginanAustralianhealthcaresetting.The

NHMRCexpectsthatallguidelineswillbereviewednolessthanonceeveryfiveyears.

ThispublicationreflectstheviewsoftheauthorsandnotnecessarilytheviewsoftheAustralianGovernment.

CONTENTS

Abbreviations .......................................................................................................................................... 1

Glossary of Terms.................................................................................................................................... 2

Guideline Panel Membership ................................................................................................................. 6

Summary of Clinical Recommendations, Good Practice Points, Implementation Implications and

Research Recommendations .................................................................................................................. 8

Clinical Recommendations .................................................................................................................. 8

Good Practice Points ........................................................................................................................... 8

Implementation Implications ............................................................................................................ 10

Research Recommendations ............................................................................................................ 12

Chapter 1: Need for these Guidelines................................................................................................... 14

Chapter 2: Summary of Guideline Development Process..................................................................... 16

Chapter 3: Background ......................................................................................................................... 17

Chapter 4: Improving Health Outcomes for the Fetus, Infant, and Child (Question 1) ........................ 20

Chapter 5: Adverse Outcomes for the Women (Question 2) ............................................................... 22

Chapter 6: Adverse Outcomes for Fetus, Infant, and Child (Question 3) ............................................. 23

Chapter 7: Summary of Evidence for Questions 1-3 ............................................................................. 24

Chapter 8: Gestational Age (Question 4) .............................................................................................. 26

Chapter 9: Timing (Question 5) ............................................................................................................. 28

Chapter 10: Regimens (Question 6) ...................................................................................................... 31

Chapter 11: Number of Babies in Utero (Question 7) .......................................................................... 36

Chapter 12: Reasons Women (at less than 30 weeks gestation) Considered at Risk of Preterm Birth

(Question 8) .......................................................................................................................................... 38

Chapter 13: Parity (Question 9) ............................................................................................................ 39

Chapter 14: Mode of Birth (Question 10) ............................................................................................. 40

Chapter 15: Effect of Antenatal Corticosteroids (Question 11) ............................................................ 42

References ............................................................................................................................................ 43

References to included RCTs ............................................................................................................. 43

Other References .............................................................................................................................. 46

Appendix A: Process and Methods ....................................................................................................... 50

Appendix B: How to use the NHMRC Evidence Statement Form ......................................................... 54

Appendix C: NHMRC Evidence Statement Form ................................................................................... 56

Appendix D: New Zealand Processes .................................................................................................... 60

Appendix E: Tocolysis Intent and Maternal Neuroprotective Intent .................................................... 61

Q1-Q3: Effectiveness Summary for Cochrane Reviews .................................................................... 63

Appendix F: Evidence Statements and Tables – Questions 1 to 11 ...................................................... 65

Q1 – Q3: Effectiveness Summary For Cochrane Reviews ................................................................. 65

Q4: Gestational Age .......................................................................................................................... 71

Q5: Time Magnesium Sulphate Planned To Be Given Prior To Preterm Birth .................................. 86

Q6: Regimens .................................................................................................................................... 95

Q7: Number of babies in utero ....................................................................................................... 104

Q8: Reason for treatment ............................................................................................................... 109

Q9: Parity Of Women ...................................................................................................................... 111

Q10: Mode Of Birth ......................................................................................................................... 113

Q11: Combined Effect Of Antenatal Corticosteroids ...................................................................... 116

Appendix G: Harms – Maternal; and Fetus, Infant, and Child ............................................................ 120

Maternal Harms .............................................................................................................................. 120

Fetus, Infant and Child .................................................................................................................... 122

Appendix H: Additional Information about Regimens and Monitoring for giving Magnesium Sulphate

to Prevent Eclampsia from Clinical Practice Guidelines and Management Protocols ........................ 124

Appendix I: Public consultation comments and Panel responses ...................................................... 134

Antenatal Magnesium Sulphate For Neuroprotection National Clinical Practice Guidelines Page 1

Abbreviations

ACMI Australian College of Midwives Inc.

ACNN Australian College of Neonatal Nurses

ACP Australian College of Pharmacy

ARCH Australian Research Centre for Health of Women and Babies, The University of Adelaide

BP Blood pressure

CI Confidence interval

DNA Deoxyribonucleic acid

g Gram/s

IPD Individual patient data

IQR Interquartile range

IV Intravenous

IVH Intraventricular haemorrhage

MgSO4 Magnesium sulphate

mL Millilitre

mm Hg Millimetres of mercury

mmol/L Millimoles per litre

NHMRC National Health and Medical Research Council

NNTB Number needed to treat to benefit

NZCOM New Zealand College of Midwives

NZGG New Zealand Guidelines Group

PPROM Preterm prelabour rupture of the membranes

RANZCOG Royal Australian and New Zealand College of Obstetrics and Gynaecology

RCNA Royal College of Nursing, Australia

RCOG Royal College of Obstetricians and Gynaecologists

RCPA Royal College of Pathologists Australasia

RCT Randomised controlled trial

RNA Ribonucleic acid

RR Risk ratio

SOGC Society of Obstetricians and Gynaecologists of Canada

SOMANZ Society of Obstetric Medicine of Australia and New Zealand

soln Solution

US United States

WHA Women’s Hospitals Australasia

WHO World Health Organization


Glossary of Terms

Adverse event An adverse outcome that occurs during or after the use of a drug or other intervention but is not necessarily caused by it.

Antenatal Occurring before birth; concerned with the care and treatment of the unborn child and pregnant women.

Antenatal corticosteroids Betamethasone and dexamethasone are corticosteroids, also called glucocorticoids, given before birth (antenatally) to improve lung development and function in the fetus at risk of preterm birth.

Antepartum haemorrhage Bleeding from the vagina during pregnancy from 20 weeks’ gestation to birth.

Applicability The degree to which a body of evidence is relevant to a particular health care context.

Arm (of a clinical study) Group of individuals within a study who are allocated to one particular intervention, for example the placebo arm.

Bias Systematic (as opposed to random) – deviation of the results of a study from the ‘true’ results.

Biological plausibility A method of reasoning to suggest a causal association between a biologic factor and a particular disease or health outcome.

Bolus A large dose of a drug given by injection for the purpose of rapidly achieving the needed therapeutic concentration in the bloodstream.

Calcium channel A structure in the body which allows cells to transmit electrical charges to each other. These charges are carried on a calcium ion which can travel freely back and forth through the calcium channel.

Case-control study A study that compares people with a specific disease or outcome of interest (cases) to people from the same population without that disease or outcome (controls), and which seeks to find associations between the outcome and prior exposure to particular risk factors. This design is particularly useful where the outcome is rare and past exposure can be reliably measured. Case-control studies are usually retrospective.

Cerebral palsy Cerebral palsy describes a group of permanent disorders of the development of movement and posture, causing activity limitation, that are attributed to nonprogressive disturbances that occurred in the developing fetal or infant brain. The motor disorders of cerebral palsy are often accompanied by disturbances of sensation, perception, cognition, communication, and behaviour, by epilepsy, and by secondary musculoskeletal problems.

Clinical impact Measure of potential benefit from application of the guideline to a population.

Cochrane Library A regularly updated electronic collection of evidence-based healthcare databases, including the Cochrane Database of Systematic Reviews.

Cochrane Review/Cochrane Systematic Review

A systematic review of the evidence usually from randomised controlled trials relating to a particular health problem or healthcare intervention, produced by the Cochrane Collaboration. Available electronically as part of the Cochrane Library.

Cognitive dysfunction Poor mental function, such as, difficulties with lack of attention, memory and problem solving.

Confidence interval Gives a range of values for an unknown population outcome estimated from a study. It will depend on the number of study recruits and the variation in the outcome data. A 95% confidence interval (CI) means that if the study was repeated 100 times with a different sample of recruits and a CI calculated each time, the interval would contain

http://www.wisegeek.com/what-is-an-ion.htm

http://en.wikipedia.org/wiki/Cognition


the ‘true’ value of the population outcome 95 times.

Controls A group of patients recruited into a study that receives no treatment, a treatment of known effect, or a placebo (dummy treatment) – in order to provide a comparison for a group receiving an experimental treatment, such as a new drug.

Deoxyribonucleic Acid The molecules inside cells that carry genetic information and pass it from one generation to the next.

Developmental delay Any significant lag in a child's physical, cognitive, behavioural, emotional, or social development, in comparison with norms.

Eclampsia Seizures (convulsions) in a pregnant woman related to hypertensive disease in pregnancy.

Evidence-based The best available evidence gained from the scientific method to inform medical decision making. It seeks to assess the quality of evidence of the risks and benefits of treatments (including lack of treatment).

Evidence statement A table summarising the results of a collection of studies which, taken together, represent the evidence supporting a particular recommendation or series of recommendations in a guideline.

Fetal Of or pertaining to a fetus or to the period of its development.

Fetal compromise The fetus not being well.

Fetus The unborn young.

Gestational age The period of time between last menstrual period and birth.

Glutamate A neurotransmitter normally involved in learning and memory. It also is an excitatory neurotransmitter, which means it stimulates areas in the brain or other parts of the nervous system.

Harms Adverse effects.

Higher order More than two fetuses in the womb.

Hypermagnesaemia An abnormally elevated concentration of magnesium in the blood.

Hyporeflexia The condition of below normal or absent reflexes.

Hypotension Abnormally low blood pressure.

Hypotonia A condition of low muscle tone (the amount of tension or resistance to movement in a muscle), often involving reduced muscle strength.

Individual patient data The central collection, validation and re-analysis of ‘raw’ data from existing trials addressing the same research question to allow further exploration of patient factors or groups that are more or less likely to benefit from treatment.

Intellectual impairment A condition where powers of comprehension and information processing abilities are affected to the point where it impairs the person’s ability to perform.

Interquartile range Difference between the first quartile (25th percentile) and the third quartile (75th percentile) of an ordered range of data.

Intraventricular haemorrhage

Bleeding inside or around the ventricles, the spaces in the brain containing the cerebrospinal fluid. Intraventricular haemorrhage can be graded based on the severity of the haemorrhage. Grades 3 and 4 represent more severe haemorrhage causing ventriculomegaly or venous infarction of the brain respectively and are more likely to be associated with neurologic disability.

In utero Within the uterus.

Loading dose One or a series of doses that may be given at the onset of therapy with the aim of achieving the target concentration rapidly.

Maternal neuroprotective intent

Magnesium sulphate given to a pregnant woman with the intention of preventing eclampsia.

http://www.nlm.nih.gov/medlineplus/ency/article/003200.htm

http://en.wikipedia.org/wiki/Evidence

http://en.wikipedia.org/wiki/Scientific_method

http://en.wikipedia.org/wiki/Therapy

http://chronicfatigue.about.com/od/cfsglossary/g/neurotransmit.htm

http://en.wikipedia.org/wiki/Magnesium

http://en.wikipedia.org/wiki/Muscle_tone

http://www.businessdictionary.com/definition/quartile.html

http://www.businessdictionary.com/definition/percentile.html

http://www.businessdictionary.com/definition/range.html

http://www.businessdictionary.com/definition/data.html


Mechanical ventilation To mechanically assist or replace spontaneous breathing.

Necrotising enterocolitis A medical condition primarily seen in premature infants, where portions of the bowel undergo tissue death (necrosis).

Neonatal Pertaining to the newborn period which is the first four weeks after birth.

Neonate An infant in the first 4 weeks of life.

Neurologic impairment A group of disorders that relate to the central nervous system (brain and spinal cord). Among the more common diagnostic categories for children are cerebral palsy, epilepsy, blindness, deafness and developmental delay. A neurological impairment may affect an individual’s speech, motor skills, vision, memory, hearing, muscle actions and learning abilities.

Neurons Primary, impulse conducting cells of the nervous system; nerve cells.

Neuroprotection A therapeutic strategy aimed at protecting neurons from injury or degeneration.

Neuroprotective intent Magnesium sulphate given to women at risk of preterm birth helps to protect the baby’s brain and improve long-term outcomes.

Nifedipine Vasodilator agent (calcium channel blocker).

Number needed to treat to benefit

The number of patients who need to be treated with the new or intervention treatment (rather than the control treatment) for one patient to benefit from the new treatment.

Observational studies A study in which the investigators do not seek to intervene, and simply observe the course of events. Changes or differences in one characteristic (e.g. whether or not people received the intervention of interest) are studied in relation to changes or differences in other characteristic(s) (e.g. whether or not they died), without action by the investigator. There is a greater risk of selection bias than in experimental studies.

Odds In a simple situations the odds of an outcome are given by the number with the outcome divided by the number without the outcome.

Odds ratio The odds of the outcome in the intervention group to the odds of an outcome in the control group.

Oxidative phosphorylation The process during which nutrients are broken down into ATP (adenosine triphosphate) using the oxygen we breathe.

Parity The number of times a women has given birth to a fetus with a gestational age of 20 weeks or more, regardless of whether the child was born alive or was stillborn.

Peripheral vasodilator Medicines that act directly on muscles in blood vessel walls to make blood vessels widen (dilate).

Periventricular leukomalacia

A form of brain injury characterised by the death of white matter near the cerebral ventricles in newborns due to damage and softening of the brain tissue.

Placebo An inactive substance or preparation used as a control in an experiment or test to determine the effectiveness of a medicinal drug.

Plasma membrane integrity Integrity of body cell walls.

Post hypoxic brain injury Damage to the brain that impairs normal functions due to lack of oxygen.

Pre-eclampsia A pregnancy-induced condition, which can occur in the second half of pregnancy. It is characterised by high blood pressure, swelling that happens suddenly along with rapid weight gain due to fluid retention, and protein in the urine.

Preterm birth The birth of a baby of less than 37 weeks’ gestational age.

Preterm labour Labour before 37 weeks’ gestation.

Protein synthesis The process by which the genetic code puts together proteins in the cell.

p-value Used in hypothesis testing where initially it is assumed that there is no difference between two treatments. The p-value is the probability that the difference observed

http://en.wikipedia.org/wiki/Respiration_(physiology)

http://en.wikipedia.org/wiki/Premature_birth

http://en.wikipedia.org/wiki/Infant

http://en.wikipedia.org/wiki/Necrosis

http://en.wikipedia.org/wiki/White_matter

http://en.wikipedia.org/wiki/Cerebral_ventricles

http://en.wikipedia.org/wiki/Cerebral_ventricles

http://www.babycenter.com.au/pregnancy/complications/bloodpressure/

http://en.wikipedia.org/wiki/Birth

http://en.wikipedia.org/wiki/Baby

http://en.wikipedia.org/wiki/Gestational_age


in a study between the two treatments might have occurred by chance. Small p-values indicate evidence against an assumption of no difference. Large p-values indicate insufficient evidence against the assumption of no difference between treatments NOT that there is actually no difference between the treatments. P-values will depend on study size; large studies can detect small differences for instance.

Randomised controlled trial

A comparative study in which participants are randomly allocated to intervention and control groups and followed up to examine differences in outcomes between the groups.

Reduction in risk The extent to which a treatment reduces a risk of an outcome, in comparison with patients not receiving the treatment of interest.

Regimens A pattern of treatment e.g. dose, frequency of a drug.

Respiratory depression The rate and/or depth of respiration are insufficient to maintain adequate gas exchange in the lungs.

Ribonucleic acid One of two types of nucleic acid made by cells. It contains information that has been copied from DNA (the other type of nucleic acid). Many forms of ribonucleic acid have functions related to making proteins.

Risk The probability of an outcome which is given by the number with the outcome divided by the number with AND without the outcome.

Risk of bias Bias in the reported outcomes of a study may be caused by an inadequacy in the way the study is designed or conducted. For example, if any of the following aspects of the trial were not conducted properly then the trial may be said to have an increased risk of bias: the random allocation of the treatments, allocation concealment, blinding of researchers during invention and measurement of outcomes, missing outcome data, selective outcome reporting.

Risk ratio The ratio of risks in two treatment groups. In intervention studies, it is the ratio of the risk in the intervention group to the risk in the control group. A risk ratio of one indicates no difference between comparison groups. For undesirable outcomes, a risk ratio that is less than one indicates that the intervention was effective in reducing the risk of that outcome. (Also called relative risk, RR.).

Sample size The number of units (persons, animals, patients, specified circumstances, etc.) in a population to be studied. The sample size should be big enough to have a high likelihood of detecting a true difference between two groups.

Singleton A single baby.

Stillbirth Death in a fetus >400g or at least 20 weeks’ gestation age.

Substantial gross motor dysfunction

The inability to make the purposeful movements of the large muscles that are necessary to complete or master a prescribed task.

Synergistic effect Interaction between drugs that has a positive effect on an outcome.

Systematic review A review of a clearly formulated question that uses systematic and explicit methods to identify, select, and critically appraise relevant research, and to collect and analyse data from the studies that are included in the review. Statistical methods (meta-analysis) may or may not be used to analyse and summarise the results of the included studies.

Therapeutic range A concentration range that provides efficacy without unacceptable toxicity.

Tocolysis The inhibition of contractions of the uterus during labour.

Tocolytic A medication that can inhibit the contractions of the uterus during labour.

http://www.biology-online.org/dictionary/Number

http://www.biology-online.org/dictionary/Units

http://www.biology-online.org/dictionary/Persons

http://www.biology-online.org/dictionary/Animals

http://www.biology-online.org/dictionary/Patients

http://www.biology-online.org/dictionary/Population

http://www.biology-online.org/dictionary/Studied

http://www.biology-online.org/dictionary/Sample

http://www.biology-online.org/dictionary/Size

http://www.biology-online.org/dictionary/Big

http://www.biology-online.org/dictionary/High

http://www.biology-online.org/dictionary/Likelihood

http://www.biology-online.org/dictionary/Difference

http://www.biology-online.org/dictionary/Groups


Guideline Panel Membership

Members Expertise Work affiliation

Chairperson

Professor Caroline Crowther*

Maternal Fetal Medicine Specialist

Professor Maternal and Fetal Medicine, Director of the Australian Research Centre for Health of Women and Babies (ARCH), Discipline of Obstetrics and Gynaecology, The University of Adelaide

Ms Philippa Middleton* Epidemiologist

Research Methodologist

Research Leader with ARCH, Discipline of Obstetrics and Gynaecology, The University of Adelaide

Ms Tanya Bubner* Researcher Manager of ARCH, Discipline of Obstetrics and Gynaecology, The University of Adelaide

Dr Helena Oakey* Statistician Senior Statistician with ARCH, Discipline of Obstetrics and Gynaecology, The University of Adelaide

Ms Mary Paleologos Administrative Assistant Administration Assistant with ARCH, Discipline of Obstetrics and Gynaecology, The University of Adelaide

Dr Lisa Askie* Epidemiologist Senior Research Fellow/Manager, Australian New Zealand Clinical Trials Registry, NHMRC Clinical Trials Centre, University of Sydney

Professor Jonathan Morris* Maternal Fetal Medicine Subspecialist

Professor of Obstetrics and Gynaecology, Head of Discipline, Obstetrics, Gynaecology and Neonatology, University of Sydney

Professor Lex Doyle* Neonatologist

Developmental Paediatrician

Professor, Obstetrics and Gynaecology, University of Melbourne

Associate Professor Vicki Flenady* Epidemiologist

Research Methodologist

Neonatal Nurse

Mater Mothers’ Research Centre, Mater Health Services, University of Queensland

Mr Neil Hotham Senior Pharmacist Drug Information Specialist

Senior Specialist Drug Information Pharmacist, Women's and Children's Hospital, Adelaide

Ms Allison Rogers Midwife/SA Perinatal Practice Guidelines

Project Midwife, SA Perinatal Practice Guidelines, Women's and Children's Hospital, Adelaide

Professor Peter Davis* Neonatologist,

Royal Australian College of Physicians (RACP) representative

Consultant Neonatologist, Royal Women’s Hospital, University of Melbourne

Professor Lesley McCowan Maternal Fetal Medicine Subspecialist

Head of Department, Sub-specialist in Maternal Fetal Medicine, Department of Obstetrics and Gynaecology, University of Auckland


Dr Jane Alsweiler Neonatologist Senior Lecturer in Paediatrics, University of Auckland

Ms Ruth Martis Midwife/New Zealand College of Midwives Representative/Lecturer

Lecturer, Christchurch Polytechnic Institute of Technology

Dr Dell Horey Epidemiologist

Consumer representative

Research Fellow, La Trobe University

Ms Rowena Crawford Consumer representative

Life’s Little Treasures Inc.

Ms Sonia Alix Consumer representative

Liggins Institute, University of Auckland

Associate Professor Susan Walker Royal Australian and New Zealand College of Obstetrics and Gynaecology (RANZCOG) representative

University of Melbourne

Dr Trudi Mannix Australian College of Neonatal Nurses (ACNN) Representative

Lecturer, Nursing and Midwifery, Flinders University

Professor David Ellwood Women’s Health Australasia (WHA) representative

Deputy Dean & Professor of Obstetrics & Gynaecology, The Australian National University Medical School, The Canberra Hospital

Ms Sarah McIntyre Cerebral Palsy Representative

Research Fellow, NSW/ACT CP Register

Cerebral Palsy Institute

University of Notre Dame Australia

* Executive panel members


Summary of Clinical Recommendations, Good Practice Points,

Implementation Implications and Research Recommendations

Clinical Recommendations

This set of clinical recommendations needs to be considered as a whole – recommendations should

not be applied in isolation.

CLINICAL RECOMMENDATIONS GRADE

Chapter

In women at risk of early preterm* imminent# birth, use magnesium

sulphate for neuroprotection of the fetus, infant and child:

* when gestational age is less than 30 weeks. #

when early preterm birth is planned or definitely expected within

24 hours. (When birth is planned, commence magnesium sulphate

as close to four hours before birth as possible).

A 4-7

B 8

A 9

intravenously with a 4 gram loading dose (slowly over 20-30 minutes) and 1 gram per hour maintenance dose via intravenous route, with no immediate repeat doses. Continue regimen until birth or for 24 hours, whichever comes first.

C 10

regardless of plurality (number of babies in utero). B 11

regardless of the reason women (at less than 30 weeks’ gestation) are considered to be at risk of preterm birth.

B 12

regardless of parity (number of previous births for the woman). B 13

regardless of anticipated mode of birth. B 14

whether or not antenatal corticosteroids have been given. B 15

Good Practice Points

Timing (Chapter 9)

If birth before 30 weeks is planned or expected to occur sooner than four hours (e.g. scheduled

caesarean or late presentation to hospital), administer magnesium sulphate to women at risk of

preterm birth, as there is still advantage likely from administration within this time.

Urgent delivery (Chapter 10)

In situations where urgent delivery is necessary because of actual or imminent maternal or fetal

compromise (e.g. severe fetal distress or antepartum haemorrhage), then birth should not be

delayed to administer magnesium sulphate.


Repeat doses (Chapter 10)

In the event that birth does not occur after giving magnesium sulphate for neuroprotection of the

infant, and preterm birth (less than 30 weeks’ gestation) again appears imminent (planned or

definitely expected within 24 hours), a repeat dose of magnesium sulphate may be considered at the

discretion of the attending health professional.

Locations of administration of antenatal magnesium sulphate (Chapter 10)

The locations of administration of antenatal magnesium sulphate intravenously to women should be

determined by each individual maternity facility.

Monitoring (Chapter 10)

During administration of magnesium sulphate intravenously, women should be regularly assessed as

detailed in individual obstetric unit protocols. Resuscitation and ventilatory support should be

immediately available, if needed, during administration of magnesium sulphate. Should hypotension

or respiratory depression occur prompt medical review is recommended. This may include cessation

of magnesium sulphate.

Loading

A minimum assessment should include checking pulse, blood pressure, respiratory rate and patellar

reflexes before loading dose, 10 minutes after loading dose infusion has started and at the end of

the loading dose infusion (20-30 minutes). The infusion should be stopped if respiratory rate

decreases more than 4 breaths per minute below baseline, or is less than 12 breaths per minute; or

diastolic blood pressure decreases more than 15 mm Hg below baseline level.

Maintenance

While the maintenance infusion is running, observe for any adverse effects. The minimum

assessments should include checking pulse, blood pressure, respiratory rate, patellar reflexes and

urine output 4-hourly. Stop infusion if respiratory rate is less than 12 breaths per minute; if patellar

reflexes are absent, if hypotension occurs or if urine output is less than 100 mL over 4 hours.

Toxicity

Magnesium toxicity is unlikely with the regimens recommended in these guidelines and serum

magnesium concentrations do not need to be routinely measured (RCOG 2006). In women with

renal compromise, serum magnesium monitoring is recommended.

Calcium gluconate (1 g (10 mL of 10% solution) slowly via intravenous route over 10 minutes) can be

given if there is clinical concern over respiratory depression.

Potential interactions (Chapter 10) There is a potential theoretical interaction between magnesium sulphate and nifedipine of

hypotension and neuromuscular blockade effects, although this is seldom reported in clinical

practice (Snyder & Cardwell 1989; Ben-Ami 1994). Regular monitoring of the mother is

recommended as detailed in individual obstetric unit protocols. If hypotension occurs, nifedipine

and magnesium sulphate administration should cease and the woman reviewed by a medical

practitioner.


Implementation Implications

Changes in usual care (Chapter 7)

While intravenous magnesium sulphate administration is standard care to prevent and treat

eclampsia, only a few obstetric units in Australia and New Zealand are using antenatal magnesium

sulphate for fetal, infant, and child neuroprotection.

Resource implications (Chapter 7) Although magnesium sulphate is an inexpensive drug, setting up, maintaining and monitoring

magnesium sulphate infusions will incur additional staff time. There will also be training needs, but

these should be minimal as all units will have experience with magnesium sulphate infusions to treat

or prevent eclampsia.

Less than 1.2% of all births occur at before 30 weeks’ gestation; around 3528 such births occur in

Australia (AIHW 2009) and 640 in New Zealand each year. Up to 10% of these babies will have been

exposed in utero to magnesium sulphate as treatment for prevention and treatment of eclampsia. If

all other women who gave birth before 30 weeks’ gestation were given magnesium sulphate for

neuroprotection of the fetus, infant, and child, up to 4104 more women in Australia and New

Zealand each year would need additional care and monitoring. (This figure does not include a small

number of women at less than 30 weeks’ gestation where birth is planned or definitely expected

within 24 hours and who do not actually give birth before 30 weeks’ gestation).

On the other hand, fewer cases of cerebral palsy will mean substantial savings at the overall health

systems and societal level.

Changes in the way care is currently organised (Chapter 7)

It is acknowledged that while all tertiary obstetric units dealing with babies likely to be born at or

before 30 weeks will already have established protocols and systems that will enable them to

administer magnesium sulphate intravenously to women at risk of preterm birth less than 30 weeks’

gestation, appropriate staffing structures may not be in place to enable the safe administration of

magnesium sulphate.

The ideal setting for babies to be born before 30 weeks is a tertiary specialist unit. Given that the

clinical indication for magnesium sulphate is planned or definitely expected preterm birth before 30

weeks then its use will generally be within tertiary obstetric units. Women threatening to give birth

before 30 weeks in other settings, and fulfilling all other guideline criteria, may be eligible to receive

magnesium sulphate after consultation with their tertiary obstetric network, depending on the non-

tertiary unit’s service capability and staffing.

Magnesium sulphate infusions should not be used during antenatal transfer unless resuscitation and

ventilator support are immediately available. If a clinical decision is made to transfer a woman who

has received magnesium sulphate in another setting to a tertiary obstetric unit, the magnesium

sulphate maintenance infusion can be stopped during the transfer.

Barriers to implementation (Chapter 7, 8 and 10)

Barriers to implementation will include finding the extra time and staff required to administer

magnesium sulphate to more women. However, as magnesium sulphate infusions, in the regimens


recommended, are already widely practised for treatment of severe pre-eclampsia and eclampsia at

these gestational ages, training needs should be minimal as all units will have experience.

Monitoring women after they have received antenatal infusions of magnesium sulphate is usually

recommended. Monitoring formed part of the published study methods for two of the included

randomised controlled trials (Crowther 2003 and Marret 2006, also see Appendix H.] There is,

however, no consensus on what form this monitoring should take. For example the Society of

Obstetric Medicine of Australia and New Zealand (SOMANZ) state that obstetric units should

determine their own protocols for monitoring outcomes [SOMANZ 2008, also see Appendix H]. As

toxicity is unlikely with the regimens recommended in these guidelines, routine monitoring of serum

magnesium sulphate concentrations should not be required.


Research Recommendations

These research recommendations have been derived from Panel discussions during the course of

developing the Guidelines.

Prevention of Cerebral Palsy

How to prevent cerebral palsy and identifying causes and causal pathways are priority research

questions.

Follow up of children in existing trials

Continuing the follow up of children in the existing randomised trials is necessary to elucidate if the

benefits from antenatal magnesium sulphate seen in early childhood translate into later benefits.

Audit of antenatal magnesium sulphate use and rates of cerebral palsy

It will be important to monitor the antenatal use of magnesium sulphate for neonatal

neuroprotection, ideally through national audit; and to link data to national childhood cerebral palsy

registers and databases.

Existing trials

Individual triallists should be approached to provide unpublished data, for subsequent revisions of

the Cochrane review ‘Magnesium sulphate for women at risk of preterm birth for the

neuroprotection of the fetus’ (Doyle 2009), where possible, on:

optimal timing of magnesium sulphate administration.

optimal treatment regimens.

gestational age breakdown or available gestational age subgroups (at trial entry).

reasons women were considered to be at risk of preterm birth and health outcomes.

plurality and health outcomes.

parity and health outcomes.

mode of birth and health outcomes.

use of antenatal corticosteroids and health outcomes.

Individual patient meta-analyses

Individual patient meta-analyses through an international collaboration of triallists responsible for

the existing randomised trials will permit further exploration of:

gestational age when magnesium sulphate was administered and health outcomes.

whether differences in timing of magnesium sulphate administration result in

differences in outcomes such as cerebral palsy and combined death and cerebral

palsy.

whether different magnesium sulphate regimens result in different rates of adverse

outcomes such as cerebral palsy and combined death and cerebral palsy.

whether differences in plurality result in different rates of adverse outcomes such as

cerebral palsy and combined death and cerebral palsy.


whether differences in reasons women were considered to be at risk of preterm

birth result in different rates of adverse outcomes such as cerebral palsy and

combined death and cerebral palsy.

influence of parity.

whether mode of birth modifies neurodevelopmental outcomes.

whether differences in use of antenatal corticosteroids result in different rates of

adverse outcomes such as cerebral palsy and combined death and cerebral palsy.

Biomarkers for cerebral palsy

Investigations to identify biomarkers for cerebral palsy in at risk groups to allow a more targeted use

of antenatal administration of magnesium sulphate.

Further randomised controlled trials

Further randomised trials are needed, comparing antenatal magnesium sulphate with placebo when

given to women at risk of preterm birth at 30 weeks’ gestation or more, that assess mortality,


Further randomised controlled trials are required specifically comparing:

different speeds of administering the loading dose of magnesium sulphate to

establish if slower loading reduces maternal adverse effects.

optimal timing of the antenatal administration of magnesium sulphate prior to

preterm birth.

loading dose versus loading dose plus maintenance.

different loading doses (4 g versus 6 g).

use of repeat doses of magnesium sulphate.

treatment of the very preterm infant with magnesium sulphate after birth.


Chapter 1: Need for these Guidelines

It is now 14 years since the publication of a case-control study first described the association of

antenatal magnesium sulphate prior to preterm birth and the prevention of cerebral palsy (Nelson

1995). The evidence available on this topic has been growing and has recently reached a

translational ‘flashpoint’. With the recent publication of the US trial (Rouse 2008), the updated

Cochrane review ‘Magnesium sulphate for women at risk of preterm birth for the neuroprotection of

the fetus’ (Doyle 2009) shows, for the first time, that magnesium sulphate given to women prior to

preterm birth can reduce the risk of cerebral palsy. This Cochrane review now contains five trials

(including the Australian and New Zealand randomised trial of antenatal magnesium sulphate for

neuroprotection of the fetus, funded through the National Health and Medical Research Council

(NHMRC) Project Grant 3503267 (Crowther 2003)).

The updated Cochrane review concludes that antenatal magnesium sulphate therapy given to

women at risk of preterm birth substantially reduced the risk of cerebral palsy in their child (risk

ratio (RR) 0.68 95% confidence interval (CI) 0.54 to 0.87; five trials, 6145 infants).

This is a very important finding, as few interventions have been found to prevent cerebral palsy

which can have devastating and long-term consequences. Over 120 children are diagnosed with

cerebral palsy in New Zealand each year and over 600 are similarly diagnosed in Australia. About

45% of all cases of cerebral palsy are related to preterm birth. Preventing cerebral palsy and

identifying causes and causal pathways have been identified as the lead priority for research by

consumers, clinicians and researchers (McIntyre 2009).

The prevention of cerebral palsy fits within the ‘Promoting and maintaining good health’ National

Research Priority; three of the four goals of this Priority are relevant, specifically;

a healthy start to life;

ageing well, ageing productively; and

preventive health.

Aim of the guideline

While it is now clear that magnesium sulphate has a role in reducing the risk of cerebral palsy, the

evidence for how and when to use magnesium sulphate is less clear. Colleges (such as the Royal

Australian and New Zealand College of Obstetricians and Gynaecologists), societies and individual

hospitals and clinicians have requested detailed evidence-based guidance in the form of a national

statement.

These Antenatal Magnesium Sulphate Prior to Preterm Birth for Neuroprotection of the Fetus,

Infant, and Child Guidelines specifically address whether the administration of magnesium sulphate

to women prior to preterm birth:

improves the health outcomes for the fetus, infant and child;

causes adverse outcomes for the women; or the fetus, infant and child;


varies by:

o gestational age magnesium sulphate is given;

o time magnesium sulphate is planned to be given prior to birth;

o regimen (dosing and routes of administration);

o number of babies in utero;

o reason women are considered to be at risk of preterm birth;

o parity of the women;

o mode of birth and interaction with magnesium sulphate;

o combined effect of antenatal corticosteroids and magnesium sulphate.

Outcomes to be considered:

Death and any neurological impairment (including cerebral palsy, blindness, deafness,

developmental delay) for the fetus/infant/child.

Harmful effects by the therapy for the woman and the child (maternal respiratory

depression, cardiac arrest, hypotension, side effects, and fetal/neonatal side effects.

Our purpose and rationale is to provide practical evidence-based guidance on the best practice for

clinical care in the use of magnesium sulphate prior to preterm birth. These guidelines will be

relevant for health professionals who care for women at risk of preterm birth and their babies; for

pregnant women and their partners and families; and for policy makers in maternity care.


Chapter 2: Summary of Guideline Development Process

A multidisciplinary expert advisory panel (the Panel) was established to oversee the development of

these Guidelines (see p.7-8 for a list of members and their roles and affiliations).

The purpose of the Panel was to prepare an evidence-based guideline on best practice for clinical

care in the use of antenatal magnesium sulphate prior to preterm birth for the neuroprotection of

the fetus, infant and child.

The Guideline was developed according to the requirements of the Australian National Health and

Medical Research Council (NHMRC) and the New Zealand Guidelines Group (NZGG) – see appendices

A and D.

The Panel formulated a set of critical clinical questions which formed the framework for the

Guidelines (these questions are listed in Chapter 1). Each question is addressed in a separate

chapter* using the following format:

a description of the studies comprising the relevant evidence;

the main results from these studies;

a summary of the judgements from the evidence statements (see below);

using judgements to formulate recommendations (and good practice points);

the implications for implementing the recommendations;

further research required to address the specific question adequately.

*For Question 1 (Does administration of magnesium sulphate prior to preterm birth improve the

health outcomes for the fetus, infant, and child?) these components are included in four chapters

(Chapters 4-7).

Summary of timeline:

12 Oct 2009 - input sought by email from full panel.

16 Oct 2009 - subsequent drafts discussed by teleconference.

12 Nov 2009 - face to face meeting in Sydney.

12 Dec 2009 - open meeting in Adelaide.

19 Dec 2009 to 18 Jan 2010 - public consultation of draft guidelines.

Feb 2010 - final guideline document.

March 2010 – draft guidelines released.

17 November 2010 – NHMRC approved guidelines.

Updating the Guidelines

One source of new evidence in the future will be an individual patient data (IPD) meta-analysis.

Funding has been awarded through a NHMRC Project Grant to commence in 2010 (NHMRC 627228).

Therefore we anticipate a major update of these Guidelines in approximately two years using data

from the IPD.


Chapter 3: Background

Cerebral palsy and link with preterm birth

Cerebral palsy and cognitive dysfunction are the most frequently occurring neurologic impairments

associated with preterm birth (before 37 weeks gestation), and any therapy that can reduce their

prevalence would substantially reduce overall neurologic impairments and disabilities among

surviving preterm infants. The cost to the Australian community of cerebral palsy including financial

cost and lost wellbeing is AUD$3.87 billion per annum. For the individual the financial and lost

wellbeing cost per annum is over AUD$115,000 (Access Economics 2008).

Cerebral palsy is a term which includes a number of different diseases or conditions that can arise at

any time during brain development. Cerebral palsy can involve a disorder of movement or posture,

or both, and a disorder of motor function which is permanent but may change over time (Oxford

Register 2001).

Approximately 42% of all cases of cerebral palsy are associated with preterm birth (Australian

Cerebral Palsy Register Group 2009) with the rate of cerebral palsy amongst neonatal survivors born

at less than 28 weeks gestation up to 30 times higher compared with infants born at term (Stanley

1992).

At present there is no cure for cerebral palsy, which makes effective preventive interventions of

paramount importance. Prevention of cerebral palsy has been identified by consumers, clinicians

and researchers as a top priority for research by the Cerebral Palsy Institute (McIntyre 2009).

Preterm birth and neurological outcome

Babies born preterm have a higher chance of dying in their first few weeks of life. Preterm infants

who survive have greater risk of neurologic impairments, such as cerebral palsy, blindness, deafness,

or cognitive dysfunction (either intellectual impairment or developmental delay), and a greater risk

of substantial disability as a result of these neurologic impairments (Doyle 2001; Saigal & Doyle

2008). Intraventricular haemorrhage (IVH) is a known risk factor for the later development of

cerebral palsy (Kuban 1992). The risk of IVH and periventricular leukomalacia increases the earlier

the gestational age at birth (Vermeulen 2001).

The rate of preterm birth is increasing in many countries, with recently reported rates of 12.8% in

the United States (National Center for Health Statistics 2009); over 8% in Australia (AIHW 2009) and

over 7% in New Zealand (New Zealand Health Information Service 2006), with corresponding

increases in the number of babies at risk of death or an adverse neurological outcome.

Biological plausibility for use of magnesium sulphate for fetal and infant neuroprotection

In humans, magnesium sulphate is essential for health through key cellular processes, including

glycolysis, oxidative phosphorylation, protein synthesis, DNA and RNA aggregation and maintenance

of plasma membrane integrity (Mildvan 1987; McIntosh et al 1989).

Animal studies have shown that magnesium sulphate can provide a neuroprotective effect

(McDonald 1990) preventing post-hypoxic brain injury by blocking the excess release of glutamate in

the calcium channel. The fetal and newborn brain seems more susceptible to damage from

http://www.mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD004661/bibliography.html#CD004661-bbs2-0031




glutamate release. Consequently, blocking glutamate receptors through agents, such as magnesium

sulphate, may reduce the risk of injury in the perinatal period (Espinoza 1991).

Possible role of magnesium sulphate for neuroprotection of the fetus, infant and child

Kuban and colleagues were the first to report that antenatal magnesium sulphate was associated

with a reduction in the risk of IVH in babies born with birthweights less than 1500 g (Kuban 1992). A

case-control analysis from the California Cerebral Palsy project investigated whether in utero

exposure to magnesium sulphate was associated with a lower prevalence of cerebral palsy among

infants born weighing less than 1500 g (Nelson 1995). Cases were singleton children with cerebral

palsy whose birthweight was less than 1500 g. Controls were randomly sampled from live births of

less than 1500 g from the same birth populations. Magnesium sulphate given to mothers during

labour was associated with a significantly marked reduction in the risk of cerebral palsy (odds ratio

0.14; 95% confidence interval 0.05 to 0.51).

Other observational studies have supported a reduction in cerebral palsy in preterm infants by

maternal administration of magnesium sulphate (Hauth 1995; Schendel 1996; Wiswell 1996) or

found a reduction in the risk of IVH (Finesmith 1997; Perlman 1994; Wiswell 1996) and perinatal

mortality (Grether 1998). However, not all observational studies have reported benefit for antenatal

magnesium sulphate for the risk of IVH (Canterino 1999; Kimberlin 1998; Paneth 1997; Weintraub

2001), cerebral palsy (Grether 2000; O'Shea 1998; Paneth 1997) or paediatric mortality (Kimberlin

1998).

Maternal adverse effects and side effects

Magnesium sulphate produces flushing, sweating, and a sensation of warmth by its peripheral

vasodilator effects when infused intravenously. Other reported maternal side effects, related to

dosage and speed of infusion, include nausea, vomiting, headache, palpitations and, rarely,

pulmonary oedema. Administration of magnesium sulphate to concentrations above the

recommended therapeutic range can lead to respiratory depression, respiratory arrest, cardiac

arrest and death.

Fetal, neonatal and infant adverse effects and side effects

In the neonate, hypermagnesaemia can lead to hyporeflexia, poor sucking, and, rarely, respiratory

depression needing mechanical ventilation (Levene 1995; Lipsitz 1971).

Magnesium sulphate use in pregnancy

The focus of these Guidelines is antenatal use of magnesium sulphate for neuroprotection of the

fetus, infant and child. The evidence for the effectiveness of magnesium sulphate for this purpose

comes from four trials (Crowther 2003; Marret 2006; Mittendorf 2002; Rouse 2008) which have

been pooled in the Cochrane systematic review ‘Magnesium sulphate for women at risk of preterm

birth for neuroprotection of the fetus’ (Doyle 2009).

Magnesium sulphate has also been used antenatally for:

Tocolysis (to inhibit contractions in threatened preterm labour)

In the relevant randomised trials from the Cochrane systematic review ‘Magnesium sulphate for

preventing preterm birth in threatened preterm labour’, Crowther 2002 found magnesium

sulphate to be ineffective at delaying birth or preventing preterm birth, and its use was
























associated with an increased mortality for infants. (Preliminary results for the update of this

Cochrane review [currently in draft form] again indicate that magnesium sulphate was

ineffective at delaying or preventing preterm birth although no significant differences in fetal,

neonatal, infant or total mortality between magnesium sulphate and placebo/no treatment or

between magnesium sulphate and other drugs used for tocolysis were seen);

Maintenance therapy for preventing preterm birth after threatened preterm labour

In the Cochrane systematic review ‘Magnesium maintenance therapy for preventing preterm

birth after threatened preterm labour’ Crowther 1998 found insufficient evidence of any

differences between magnesium sulphate maintenance therapy and either placebo/no

treatment, or alternative therapies (ritodrine or terbutaline) to prevent preterm birth after an

episode of threatened preterm labour;

Neuroprotection of the mother (to prevent and treat pre-eclampsia)

The Cochrane systematic review ‘Magnesium sulphate and other anticonvulsants for women

with pre-eclampsia’ (Duley 2003) found that magnesium sulphate more than halved the risk of

eclampsia and probably reduced the risk of maternal death, but did not improve outcomes for

the baby in the short term.

Evidence summaries for the tocolytic and maternal neuroprotective use of magnesium sulphate can

be found in Appendix E.

Evidence relating to possible harms to the mother or the fetus/infant/child from any antenatal use

of magnesium sulphate (compared with placebo or no treatment) will be considered later (see

Chapters 5 and 6 and Appendix G).


Chapter 4: Improving Health Outcomes for the Fetus, Infant,

and Child (Question 1)

Question 1: Does the administration of magnesium sulphate to women prior to preterm birth improve the health outcomes for the fetus, infant, and child?

Magnesium sulphate is given to pregnant women at risk of preterm birth with the intention of

preventing cerebral palsy and other adverse neurodevelopmental outcomes.

As foreshadowed in Chapter 3, the four trials (Crowther 2003, Marret 2006, Mittendorf 2002

(neuroprotective arm only) and Rouse 2008) in the Doyle 2009 Cochrane systematic review

‘Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus’ form the

evidence base for the effectiveness of antenatal use of magnesium sulphate for fetal, infant or child

neuroprotective intent, the focus of these guidelines.

The evidence for potential harms was taken from a wider evidence base – from studies related to

fetal, infant and child neuroprotective intent, as well as tocolytic intent and maternal

neuroprotective intent (pre-eclampsia). These studies are contained in four Cochrane reviews

(Doyle 2009, Duley 2003, Crowther 2002 and Crowther 1998) – see Chapters 5 and 6.

The evidence for effectiveness outlined in this chapter was considered with the evidence for

potential harms in Chapter 7, where there is formulation of an overall recommendation about the

use of antenatal magnesium sulphate for neuroprotection of the fetus, infant and child.

NEUROPROTECTION (FETUS, INFANT, AND CHILD)

The Doyle 2009 Cochrane review compared magnesium sulphate with placebo or no treatment given

to women at risk of preterm birth and included four trials (4446 infants) which addressed infant

neuroprotection.

Death and cerebral palsy are competing outcomes as most perinatal deaths or those deaths that

occur later before cerebral palsy can be diagnosed. Therefore, the combined outcome of death or

cerebral palsy is commonly considered the most clinically relevant outcome for assessing

neuroprotection.

In Doyle 2009, the combined outcome of death or cerebral palsy or cerebral palsy alone showed

significant reductions where women who were at risk of preterm birth were given magnesium

sulphate antenatally with the intent of providing neuroprotection (see Table 1). The review showed

that 63 babies (95% confidence interval 44 to 155) need to be treated with magnesium sulphate for

one baby to avoid cerebral palsy. The corresponding number needed to treat to benefit (NNTB) for

combined death or cerebral palsy was 42 babies (95% confidence interval 24 to 346).


Table 1: Magnesium sulphate vs placebo/no treatment: primary outcomes (Doyle 2009 Cochrane Review)

Primary outcomes RR (95% CI) Number of trials; participants

Death or cerebral palsy 0.85 (0.74 to 0.98)* four trials; 4446 infants

Death (fetal and later) 0.95 (0.80 to 1.12) four trials; 4446 infants

Cerebral palsy 0.71 (0.55 to 0.91)* four trials; 4446 infants

Any neurological impairment 1.03 (0.87 to 1.21) one trial; 1255 infants

Death or substantial gross motor dysfunction 0.84 (0.71 to 1.00) three trials; 4387 infants

*significantly in favour of magnesium sulphate

See Appendix F.1-3: Evidence tables/graphs

Table 2: Magnesium sulphate vs placebo/no treatment: selected secondary outcomes (Doyle 2009 Cochrane Review)

Secondary outcomes RR (95% CI) Number of trials; participants

Neonatal outcomes

Intraventricular haemorrhage 0.96 (0.86 to 1.08) four trials; 4552 infants

Severe intraventricular haemorrhage (grade 3/4)

0.83 (0.62 to 1.13) two trials; 3699 infants

Periventricular leukomalacia 0.93 (0.68 to 1.28) four trials; 4552 infants

Infant/child outcomes

Substantial gross motor dysfunction 0.60 (0.43 to 0.83)* three trials; 4387 infants

Development delay or intellectual impairment 1.00 (0.91 to 1.09) three trials; 4387 infants

Major neurological disability 1.14 (0.86 to 1.51) one trial; 1255 infants

Blindness 0.97 (0.14 to 6.90) two trials; 1943 infants

Deafness 0.51 (0.05 to 4.96) two trials; 1943 infants



Chapter 5: Adverse Outcomes for the Women (Question 2)

Question 2: Does the use of magnesium sulphate prior to preterm birth cause adverse outcomes for the women?

Evidence regarding potential maternal harms was extracted from those trials that compare

magnesium sulphate with placebo or no treatment in the four Cochrane reviews looking at the

various indications for antenatal use of magnesium sulphate (Crowther 1998, Crowther 2002, Doyle

2009 and Duley 2003).

Women given magnesium sulphate were about three times more likely to cease therapy compared

with women not given magnesium sulphate therapy (placebo or no treatment), mainly due to

flushing (20.4% vs 2.2%), nausea/vomiting (3.2% vs 0.4%) and headaches (0.7% vs 0.3%). Overall

cessation of therapy was 7.5% in the magnesium sulphate group compared with 2.7% in the

placebo/no treatment groups.

Hypotension (variously defined) and respiratory depression (variously defined) were also

significantly elevated among women given magnesium sulphate. Overall hypotension was 2.0% in

the magnesium sulphate groups compared to 1.2% in the placebo/no treatment groups. Overall

respiratory depression was 1.3% in the magnesium sulphate groups and 0.8% in the placebo/no

treatment groups.

In the Cochrane review on preventing eclampsia (Duley 2003), a small but significant absolute

increase of 2.5% in the caesarean rate was seen, from 47.2% in the placebo group to 49.7% in the

magnesium group (RR 1.05 95% CI 1.01 to 1.10). There was not a significant increase in the

caesarean rate in the Doyle 2009 Cochrane Review (48.8% for the magnesium sulphate group and

47.2% for the placebo group).

In very large doses, magnesium sulphate can have toxic, even life-threatening effects for women.

This has been documented in case reports (for example McDonnell 2009). Careful monitoring of the

woman’s magnesium sulphate administration is therefore advised (see Chapter 10).

See Appendix G.1: Evidence tables


Chapter 6: Adverse Outcomes for Fetus, Infant, and Child

(Question 3)

Question 3: Does the use of magnesium sulphate prior to preterm birth cause adverse outcomes for the fetus, infant, and child?

Evidence regarding potential harms to the fetus, infant or child was extracted from the trials

comparing magnesium sulphate with placebo or no treatment in the four Cochrane reviews looking

at the various indications for antenatal use of magnesium sulphate (Crowther 1998, Crowther 2002,

Doyle 2009 and Duley 2003).

None of the harms for the fetus, infant or child were significantly increased with antenatal use of

magnesium sulphate including total deaths (fetal, neonatal, or infant), intraventricular haemorrhage

or necrotising enterocolitis.

See Appendix G.2: Evidence tables


Chapter 7: Summary of Evidence for Questions 1-3

Summary of evidence statement judgements for fetal, infant, and child neuroprotection

The evidence base for using magnesium sulphate as an agent for fetal, infant, and child

neuroprotection has low risk of bias. Results between trials are fairly consistent. Benefits were

judged to outweigh potential harms and clinical impact considered to be very large, due to the

importance of reducing the risk of cerebral palsy.

While evidence was applicable to the context of Australian and New Zealand health care, it had less

generalisability in regard to the intended target population (women at risk of preterm birth) as the

majority of women in the largest trial had preterm prelabour rupture of membranes (PPROM) when

recruited to the trial (and so represented a narrower subset of women at risk of preterm birth).

Overall the body of evidence was considered sufficiently good enough to make the following grade A

recommendation:

CLINICAL RECOMMENDATION GRADE

In women at risk of early preterm* imminent# birth, use magnesium sulphate for neuroprotection of the fetus, infant and child.

*see chapter 8 #see chapter 9

A

Appendix F1-3: Evidence statements

IMPLEMENTATION IMPLICATIONS

Changes in usual care

While intravenous magnesium sulphate administration is standard care to prevent and treat

eclampsia, only a few obstetric units in Australia and New Zealand are using antenatal magnesium

sulphate for fetal, infant, and child neuroprotection.

Resource implications

Although magnesium sulphate is an inexpensive drug, setting up, maintaining and monitoring

magnesium sulphate infusions will incur additional staff time. There will also be training needs but

these should be minimal as all units will have experience with magnesium sulphate infusion to treat

or prevent eclampsia.

Less than 1.2% of all births occur at before 30 weeks’ gestation; around 3528 such births occur in

Australia (AIHW 2009) and 640 in New Zealand each year. Up to 10% of these babies will have been

exposed in utero to magnesium sulphate as treatment for prevention and treatment of eclampsia. If

all other women who gave birth before 30 weeks’ gestation were given magnesium sulphate for

neuroprotection of the fetus, infant, and child, up to 4104 more women in Australia and New

Zealand each year would need additional care and monitoring. (This figure does not include a small

number of women at less than 30 weeks’ gestation where birth is planned or definitely expected

within 24 hours and who do not actually give birth before 30 weeks’ gestation).

On the other hand, fewer cases of cerebral palsy will mean substantial savings at the overall health

systems and societal level.


Changes in the way care is currently organised

It is acknowledged that while all tertiary obstetric units dealing with babies likely to be born at or

before 30 weeks will already have established protocols and systems that will enable them to

administer magnesium sulphate intravenously to women at risk of preterm birth less than 30 weeks’

gestation, appropriate staffing structures may not be in place to enable the safe administration of

magnesium sulphate.

The ideal setting for babies to be born before 30 weeks is a tertiary specialist unit. Given that the

clinical indication for magnesium sulphate is planned or definitely expected preterm birth before 30

weeks then its use will generally be within tertiary obstetric units. Women threatening to give birth

before 30 weeks in other settings, and fulfilling all other guideline criteria, may be eligible to receive

magnesium sulphate after consultation with their tertiary obstetric network, depending on the non-

tertiary unit’s service capability and staffing.

Magnesium sulphate infusions should not be used during antenatal transfer unless resuscitation and

ventilator support are immediately available. If a clinical decision is made to transfer a woman who

has received magnesium sulphate in another setting to a tertiary obstetric unit, the magnesium

sulphate maintenance infusion can be stopped during the transfer.

Barriers to implementation

Barriers to implementation will include finding the extra time and staff required to administer

magnesium sulphate to more women. However, as magnesium sulphate infusions, in the regimens

recommended, are already widely practised for treatment of severe pre-eclampsia and eclampsia at

these gestational ages, training needs should be minimal as all units will have experience.

FURTHER RESEARCH RECOMMENDATIONS AND AUDIT

Further analyses of the existing trials (such as subgroup analyses and individual patient data

meta-analyses) will provide evidence to elucidate optimal timing of magnesium sulphate

administration and its optimal regimens (see subsequent chapters).

A randomised trial comparing different speeds of administering the loading dose of

magnesium sulphate would establish if slower loading reduces maternal adverse effects.

Investigations to identify biomarkers for cerebral palsy in at risk groups to allow a more

targeted antenatal administration of magnesium sulphate.

It will be important to monitor the antenatal use of magnesium sulphate, ideally through

national audit; and to link data to national childhood registers and databases.

School-age outcomes will be available from some studies; results of these studies may lead

to modifications of these guidelines.


Chapter 8: Gestational Age (Question 4)

Question 4: Do the improvements for the fetus, infant, and child vary by gestational age?

This chapter summarises the evidence available from the four individual neuroprotective intent trials

within the Doyle 2009 Cochrane Review that consider gestational age at trial entry and effect of

antenatal magnesium sulphate.

All women in the four trials included in the Doyle 2009 Cochrane review were given magnesium

sulphate before 34 weeks’ gestation. In Rouse 2008, all women were less than 32 weeks at trial

entry with the majority (68% of trial participants) less than 30 weeks gestation (Costantine 2009).

Table 3: Gestational age at trial entry for trials (Doyle 2009 Cochrane Review)

Study Gestational age

Mittendorf 2002 < 34 weeks at randomisation

Marret 2006 < 33 weeks

Rouse 2008 (32% of trial participants) 31- 32 weeks

Crowther 2003 & Rouse 2008 (68% of trial participants) < 30 weeks

However the data analyses published in a systematic review by Costantine 2009 did not include all

women and so only subgroup analyses for women at different gestational ages are possible at

present; women with a gestational age of less than 34 weeks, less than 33 weeks, less than 32 weeks

and less than 30 weeks. There is one trial with each subgroup available for each analysis but results

are inconclusive due to small sample sizes.

Table 4: Results of primary outcomes by gestational age subgroup (Doyle 2009 Cochrane Review)

Trial Gestational age DEATH or CEREBRAL PALSY

CEREBRAL PALSY DEATH

RR (95% CI) +Mittendorf 2002

(n=59)

< 34 weeks 4.83 (0.60 to 38.90) 6.77 (0.37 to 125.65) 1.93 (0.19 to 20.18)

Marret 2006

(n=688)

< 33 weeks 0.80 (0.58 to 1.10) 0.70 (0.41 to 1.19) 0.85 (0.55 to 1.32)

Rouse 2008

(n=2444)

< 32 weeks 0.90 (0.73 to 1.10) 0.59 (0.40 to 0.85)* 1.13 (0.87 to 1.48)

Crowther 2003

(n=1255)

< 30 weeks 0.82 (0.66 to 1.02) 0.85 (0.55 to 1.31) 0.81 (0.62 to 1.05)

OVERALL < 34 weeks 0.86 (0.75 to 0.98)* 0.71 (0.55 to 0.91)* 0.95 (0.80 to 1.12) +neuroprotective arm

See Appendix F.4 for evidence tables/graphs


Summary of evidence statement judgements for gestational age subgroup

The subgroup analyses are from trials with low risk of bias, and where results between trials are

fairly consistent. While the evidence is applicable to the Australian and New Zealand context,

generalisability was reduced as the majority of the women (87%) in the largest trial (Rouse 2008)

had PPROM and so represent a limited subset of women at risk of preterm birth.

Overall clinical impact was judged to be very large but since any differences in death and cerebral

palsy by gestational age are unclear at present, no particular subgroup was judged by the guideline

panel to have any more or less impact than another.

How recommendation was formulated To minimise the number of women exposed the guideline panel felt it would be prudent, at this

stage, to restrict magnesium sulphate administration to the subgroup containing the lowest

gestational age (less than 30 weeks) and therefore recommend that magnesium sulphate be given

only for neuroprotective intent when women are at risk of preterm birth (less than 30 weeks’

gestation).

If magnesium sulphate administration is restricted to women at less than 30 weeks’ gestation at risk

of preterm birth; this will be a smaller group than those at less than 34 weeks’ gestation, which will

have a somewhat smaller impact on resource allocations.

See Appendix F.4 for evidence statement


In women at risk of early preterm* imminent#

birth, use magnesium sulphate for neuroprotection of the fetus, infant or child:

*when gestational age is less than 30 weeks.

#see chapter 9

B


As for Chapter 7.

FURTHER RESEARCH RECOMMENDATIONS

Individual triallists should be approached to provide unpublished gestational age

breakdowns or be requested to provide available gestational age subgroup analyses.

Individual patient data meta-analysis by gestational age when magnesium sulphate was

administered and health outcomes needs to be conducted.

Further randomised trials are needed, comparing antenatal magnesium sulphate with

placebo when given to women at risk of preterm birth at 30 weeks’ gestation or more, that

assess mortality, cerebral palsy and combined death and cerebral palsy.


Chapter 9: Timing (Question 5)

Question 5: Do improvements to the fetus, infant, and child vary by time magnesium sulphate is planned to be given prior to preterm birth?

This chapter summarises the evidence available from the four individual randomised

neuroprotective intent trials included in the Doyle 2009 Cochrane Review that looked at the time

magnesium sulphate was planned to be given prior to preterm birth.

In two of the four neuroprotective intent trials (Crowther 2003 and Marret 2006), magnesium

sulphate was given when birth was planned or expected within 24 hours. The median time from

randomisation to birth for women in the magnesium sulphate group was 3.7 hours (interquartile

range (IQR) 1.4 to 13.8) for Crowther 2003 and 1 hour 38 minutes (IQR 5 minutes to 25 hours and 5

minutes) for Marret 2006. In Rouse 2008, at the time of recruitment to the study only 3% of women

were planned or expected to give birth within 24 hours. Although a further 10% were in advanced

preterm labour, most (87%) women had PPROM with a median time to birth of 25 hours (IQR 11 to

63 hours) from rupture of membranes. Mittendorf 2002 did not specify the time prior to preterm

birth in which it was planned that magnesium sulphate was to be given (although women recruited

to the study were in advanced preterm labour with cervical dilatation of more than 4 cm).

Table 5: Timing of magnesium sulphate administration for trials (Doyle 2009 Cochrane Review)

Study Timing

Crowther 2003

Marret 2006

When birth was planned or definitely expected within 24 hours

Rouse 2008 when birth was planned or expected within 24 hours for indicated preterm birth (3.1% only);

advanced preterm labour, with cervical dilatation between 4 and 8 cm (10.3%);

PPROM 86.7% - median 25 hours, interquartile range 11 to 63 hours from rupture of membranes to birth interval

Mittendorf 2002 Not specified

At present subgroup analyses are unable to provide conclusive results on the optimal timing for the

administration of magnesium sulphate prior to anticipated preterm birth.


Table 6: Results of primary outcomes by timing for trials (Doyle 2009 Cochrane Review)

See Appendix F.5: evidence tables/graphs

Summary of evidence statement judgements for timing of magnesium sulphate administration

subgroup

The subgroup analyses come from trials with low risk of bias, where the results between trials are

fairly consistent. The evidence from the subgroups in which birth was planned or expected within

24 hours (Crowther 2003 and Marret 2006) was judged to be directly generalisable to the target

population, and the overall evidence applicable.

Overall clinical impact was judged to be very large but since differences in death and cerebral palsy

based on the timing of planned magnesium sulphate administration are unclear at present, no

particular subgroup was judged to have any greater or lesser impact than another.

How recommendation was formulated

The subgroup in which preterm birth was planned or definitely expected within 24 hours (Crowther

2003 and Marret 2006) was judged to be most representative of all subgroups included in the

intended target groups for this guideline. In addition, this subgroup showed a reduction in death or

cerebral palsy (see Table 6), even though it contained only 44% of the total number of women across

all four trials. On the other hand, Rouse 2008 (with 56% of the total number of women in the

Cochrane review) individually showed a benefit for cerebral palsy with magnesium sulphate (see

table 6 above).

In a small side study of Crowther 2003, Smith 2003 found that antenatal infusions enabled prompt

transfer of magnesium sulphate to the mother (within 30 minutes) and that neonatal magnesium

sulphate concentrations remained elevated to 24 hours. This indicates that magnesium sulphate

crosses the placenta to the fetus promptly after commencing the infusion.

Based on this evidence, the guideline panel recommended that magnesium sulphate be administered when early preterm birth is planned or definitely expected within 24 hours. (When birth is planned, commence magnesium sulphate as close to four hours before birth as possible). see Appendix F.5: evidence statement

Trial Timing DEATH or CEREBRAL PALSY

CEREBRAL PALSY

DEATH

RR (95% CI)

Crowther 2003; Marret 2006 (n=1943)

If birth planned or definitely expected within 24 hours

0.81 (0.68 to 0.97)* 0.79 (0.56 to 1.10) 0.82 (0.66 to 1.03)

Rouse 2008 (n=2444)

Variable 0.90 (0.73 to 1.10) 0.59 (0.40 to 0.85)* 1.13 (0.87 to 1.48)

Mittendorf 2002 (n=59)

Not specified 4.83 (0.60 to 38.90) 6.77 (0.37 to 125.65) 1.93 (0.19 to 20.18)

OVERALL 0.86 (0.75 to 0.98)* 0.71 (0.55 to 0.91)* 0.95 (0.80 to 1.12) *significantly in favour of magnesium sulphate





#when early preterm birth is planned or definitely expected within 24 hours. (When birth is planned, commence magnesium sulphate as close to four hours before birth as possible).

*see chapter 8

A

GOOD PRACTICE POINT

If birth before 30 weeks is planned or expected to occur sooner than four hours (e.g. scheduled

caesarean or late presentation to hospital), administer magnesium sulphate to women at risk of

preterm birth, as there is still advantage likely from administration within this time.

IMPLEMENTATION IMPLICATIONS As for chapter 7.


Individual triallists should be approached to provide unpublished optimal timing of

magnesium sulphate administration

Individual patient data meta-analysis can be used to explore whether differences in timing of

magnesium sulphate administration result in different rates of adverse outcomes such as


Further randomised trials evaluating the optimal timing of the antenatal administration of

magnesium sulphate prior to preterm birth are warranted.


Chapter 10: Regimens (Question 6)

Question 6: Do improvements to the fetus, infant, and child vary by regimens?

This chapter summarises the evidence of the four individual neuroprotective intent trials in the

Doyle 2009 Cochrane Review for regimens used to administer magnesium sulphate.

In these trials, the loading doses of magnesium sulphate given were either 4 grams or 6 grams.

Two trials did not use a maintenance dose (Mittendorf 2002 and Marret 2006) and two trials gave

maintenance doses of either 1 gram per hour (Crowther 2003) or 2 grams per hour (Rouse 2008).

No repeat dosing was given in three of the four trials (Mittendorf 2002; Crowther 2003 and Marret

2006). All trials used intravenous magnesium sulphate.

Table 7: Regimens of trials (Doyle 2009 Cochrane Review)

Study Loading

Dose

Maintenance

Dose

Repeat dosing Route Actual regimen given (in magnesium group)

Marret 2006

(PREMAG)

4 g (over 30 mins) none none IV 91% (259/286) given full dose

2% (7/286) given partial dose only

7% (20/286) not given magnesium sulphate

Mittendorf 2002 (MagNET)

4 g bolus none none IV Not reported

Crowther 2003

(ACTOMgSO4)

4 g (over 20 mins) 1 g/hour;

until birth or up to 24 hours, whichever was first

none IV 91% (484/535) given full loading dose

7% (38/535) given partial loading dose

84% (451/535) started maintenance dose

2% (13/535) women not given magnesium sulphate

Rouse 2008

(BEAM)

6 g (over 20-30 mins) 2 g/hour;

stopped if birth had not occurred in 12 hours and was no longer considered imminent

If contractions recurred, infusion was resumed at 2 g/hour; if at least 6 hours had passed since the discontinuation of magnesium, another loading dose was given

IV 91% (996/1,096) given magnesium sulphate for 3 h or more

8% (82/1,096) given magnesium sulphate 3 h before birth

2% (18/1,096) not given magnesium sulphate

(42.2% given repeat dose)


There was a significant reduction in the combined outcome of death or cerebral palsy; and of

cerebral palsy across all trials (RR 0.85; 95% CI 0.74 to 0.98 and RR 0.71; 95% CI 0.52 to 0.97; 4446

infants). Rouse 2008, which was considerably larger than the other trials, significantly contributed to

the finding of the overall reduction in cerebral palsy (RR 0.59; 95% CI 0.40 to 0.85; 2444 infants).

Table 8: Results of primary outcomes by regimen for trials (Doyle 2009 Cochrane Review)

Trial Regimen DEATH OR CEREBRAL PALSY

RR (95% CI)


Marret 2006; Mittendorf 2002

(n=747)

4 g (no maintenance);

Marret 2006 (over 30 mins);

Mittendorf 2002 (bolus)

1.45 (0.27 to 7.72)

1.37 (0.18 to 10.70)

0.88 (0.57 to 1.35)

Crowther 2003

(n=1255)

4 g (over 20 mins) plus 1 g/hour maintenance

0.82 (0.66 to 1.02)

0.85 (0.55 to 1.31)

0.81 (0.62 to 1.05)

Rouse 2008

(n=2444)

6 g (over 20-30 mins) plus 2 g/hour maintenance

0.90 (0.73 to 1.10)

0.59 (0.40 to 0.85)*

1.13 (0.87 to 1.48)

OVERALL

(n=4446)

0.85 (0.74 to 0.98)*

0.71 (0.52 to 0.97)*

0.95 (0.80 to 1.12)


see Appendix F.6: evidence tables/graphs

Summary of evidence statement judgements for regimens

The evidence base for regimens used to administer magnesium sulphate to women at risk of

preterm birth for neuroprotection of their fetus, infant or child was judged to have a low risk of bias

despite some unexplained inconsistency between Marret 2006 and Mittendorf 2002 in subgroups.

For the combined outcome of death and cerebral palsy; and the outcome of cerebral palsy alone, in

the 4 g no maintenance subgroups, the effect was in opposite directions in the two trials (in favour

of magnesium sulphate in Marret, in favour of no magnesium sulphate in Mittendorf, with neither

result statistically significant).

The evidence was judged by the guideline panel to be both generalisable and applicable to the

Australian and New Zealand healthcare context.

Overall the clinical impact was judged to be very large, however, since differences in death and

cerebral palsy by regimen are unclear at present, no particular regimen subgroup was judged to

have any greater or lesser impact than another.

How the recommendation was formulated

Although the trial with higher loading dose with repeat treatment permitted (Rouse 2008) was the

only study to show statistical significance on its own (RR of cerebral palsy 0.59 95% CI 0.40 to 0.85),

it was unclear whether this was due to a dose effect or due to the size of the trial, (which was the

largest in the meta-analysis and therefore had more power to detect differences). However, the

case for a dose effect is weakened by the lack of a significant finding for the combined outcome of

death or cerebral palsy (RR 0.90 95% CI 0.73 to 1.10).


Because of this uncertainty, the guideline panel felt it prudent to restrict magnesium sulphate

administration to the lowest loading dose (4 g) used with a maintenance dose (again based on the

lowest maintenance dose of 1 g/hour). Therefore the guideline panel recommends that magnesium

sulphate should only be given for neuroprotection as a 4 g loading dose slowly over 20-30 minutes

with 1 gram per hour maintenance dose and with no immediate repeat doses, via intravenous route.

This should be continued up until birth or within 24 hours, whichever comes first.

The loading regimen of 4 g magnesium sulphate is identical to loading doses commonly used

throughout Australia, New Zealand and elsewhere to treat women with pre-eclampsia (see Appendix

H). The maintenance dose of 1 g/hr of magnesium sulphate is consistent with maintenance doses

commonly used throughout Australia and New Zealand to treat women with pre-eclampsia and

eclampsia (see Appendix H).

There is considerable variation in the method of giving the loading doses (by either infusion pump or

syringe pump). A time period of 20-30 minutes for infusion of a 4 g loading dose is recommended

for women with pre-eclampsia (see Appendix H).

Appendix F. 6: Evidence tables/graphs




intravenously with a 4 gram loading dose (slowly over 20-30 minutes) and 1 gram per hour maintenance dose via intravenous route, with no immediate repeat doses. Continue regimen up until birth or for 24 hours, whichever comes first.

*see chapter 8 #

see chapter 9

C

GOOD PRACTICE POINTS

Urgent delivery

In situations where urgent delivery is necessary because of actual or imminent maternal or fetal

compromise (e.g. severe fetal distress or antepartum haemorrhage), then birth should not be

delayed to administer magnesium sulphate.

Repeat doses

In the event that birth does not occur after giving magnesium sulphate for neuroprotection of the

infant, and preterm birth (less than 30 weeks’ gestation) again appears imminent (planned or

definitely expected within 24 hours), a repeat dose of magnesium sulphate may be considered at the

discretion of the attending health professional.

Locations of administration of antenatal magnesium sulphate (Chapter 10)

The locations of administration of antenatal magnesium sulphate intravenously to women should be

determined by each individual maternity facility.


Monitoring

During administration of magnesium sulphate intravenously, women should be regularly assessed as

detailed in individual obstetric unit protocols. Resuscitation and ventilatory support should be

immediately available, if needed, during administration of magnesium sulphate. Should hypotension

or respiratory depression occur prompt medical review is recommended. This may include cessation


Loading

A minimum assessment should include checking pulse, blood pressure, respiratory rate and patellar

reflexes before loading dose, 10 minutes after loading dose infusion has started and at the end of

the loading dose infusion (20-30 minutes). The infusion should be stopped if respiratory rate

decreases more than 4 breaths per minute below baseline, or is less than 12 breaths per minute; or

diastolic blood pressure decreases more than 15 mm Hg below baseline level (Crowther 2003).

Maintenance

While the maintenance infusion is running, observe for any adverse effects. The minimum

assessments should include checking pulse, blood pressure, respiratory rate, patellar reflexes and

urine output 4-hourly. Stop infusion if respiratory rate is less than 12 breaths per minute; if patellar

reflexes are absent, if hypotension occurs or if urine output is less than 100 mLs over 4 hours.

Toxicity

Magnesium toxicity is unlikely with the regimens recommended in these guidelines and serum

magnesium concentrations do not need to be routinely measured (RCOG 2006). In women with

renal compromise, serum magnesium monitoring is recommended.

Calcium gluconate (1 gram (10 mL of 10% solution) slowly via intravenous route over 10 minutes)

can be given if there is clinical concern over respiratory depression.

Potential interactions (Chapter 10) There is a potential theoretical interaction between magnesium sulphate and nifedipine of

hypotension and neuromuscular blockade effects (Snyder & Cardwell 1989; Ben-Ami 1994), although

this is seldom reported in clinical practice. Regular monitoring of the woman is recommended as

detailed in individual obstetric unit protocols. If hypotension occurs, nifedipine and magnesium

sulphate should cease and the woman reviewed by a medical practitioner.


Australian and New Zealand clinicians are less likely to be comfortable using loading doses higher

than 4 gram.

Monitoring women after they have been given antenatal infusions of magnesium sulphate is usually

recommended. Monitoring formed part of the published study methods for two of the included

randomised controlled trials (Crowther 2003 and Marret 2006) – see Appendix H. There is, however,

no consensus on what form this monitoring should take. For example the Society of Obstetric

Medicine of Australia and New Zealand (SOMANZ) state that obstetric units should determine their

own protocols for monitoring outcomes (SOMANZ 2008 [also see Appendix H]). As toxicity is

unlikely with the regimens recommended in these guidelines, routine monitoring of serum

magnesium sulphate concentrations should not be required.



Individual triallists should be approached to provide unpublished optimal treatment

regimens.

Individual patient data meta-analysis can be used to explore whether different magnesium

sulphate regimens result in different rates of adverse outcomes such as cerebral palsy and

combined death and cerebral palsy.

Further randomised trials of regimens are required, specifically comparing:

o loading dose versus loading dose plus maintenance

o different loading doses (4 gram versus 6 gram)

o use of repeat doses of magnesium sulphate.


Chapter 11: Number of Babies in Utero (Question 7)

Question 7: Do improvements to the fetus, infant, and child vary by number of babies in utero?

This chapter summarises the evidence from the four individual neuroprotective intent trials within

the Doyle 2009 Cochrane review for the number of babies in utero.

All four trials included twins; two trials also included higher order multiple gestations (Crowther

2003 and Marret 2006). Only Crowther 2003 and Rouse 2008 reported death separately as an

outcome for single and multiple pregnancies and only Crowther 2003 reported cerebral palsy

outcomes separately for these groups.

Table 9: Plurality of trials (Doyle 2009 Cochrane Review)

Study Single Twin Higher order Reported separately

Crowther 2003 Yes Yes Yes (triplet+quad) Single vs multiple

Rouse 2008 Yes Yes No Single vs twin++

Marret 2006 Yes Yes Yes (triplet) No

Mittendorf 2002 Yes Yes No No

Table 10: Results of primary outcomes by plurality for trials (Doyle 2009 Cochrane Review)

Number of babies in utero

DEATH or CEREBRAL PALSY


RR (95% CI)

Multiple 0.73 (0.50 to 1.08)

Crowther 2003

0.52 (0.21 to 1.25)

Crowther 2003

0.90 (0.63 to 1.31)

Crowther 2003,

Rouse 2008

Single 0.86 (0.67 to 1.11)

Crowther 2003

1.01 (0.61 to 1.68)

Crowther 2003

0.96 (0.68 to 1.37)

Crowther 2003,

Rouse 2008

Multiple and single 0.88 (0.74 to 1.05)

Marret 2006, Mittendorf 2002, Rouse 2008

0.65 (0.48 to 0.88)*

Marret 2006, Mittendorf 2002, Rouse 2008

0.88 (0.57 to 1.35)

Marret 2006, Mittendorf 2002

OVERALL 0.86 (0.75 to 0.98)* 0.71 (0.55 to 0.91)* 0.94 (0.79 to 1.12) ++

Rouse 2008 reported only moderate to severe cerebral palsy, (not all cerebral palsy) so plurality data from Rouse can only be reported for the outcome of death.

Appendix F.7: Evidence tables/graphs


Summary of evidence statement judgements for number of babies in utero subgroup of infant

neuroprotection

The subgroup analyses come from trials with low risk of bias, and results between trials are fairly

consistent. While evidence is applicable, generalisability to the Australian and New Zealand context

was reduced since the majority of the women in the largest trial had PPROM (and therefore

represented a narrower subset of women at risk of preterm birth).

Overall clinical impact was judged to be very large, but since any differences in death and cerebral

palsy by number of babies in utero is unclear at present, no particular subgroup was judged to have

any greater or lesser impact than another.

The guideline panel therefore recommends that magnesium sulphate be used regardless of plurality.

Appendix F.7: Evidence statements


In women at risk of early preterm* imminent# birth, use magnesium sulphate for neuroprotection of the fetus, infant or child:

regardless of plurality (number of babies in utero).

*see chapter 8 # see chapter 9

B


As for Chapter 7.


If triallists collected data on plurality, these data should be obtained and aggregate analyses

conducted.

Individual patient data meta-analysis can be used to explore whether differences in plurality

result in different rates of adverse outcomes such as cerebral palsy and combined death and

cerebral palsy.


Chapter 12: Reasons Women (at less than 30 weeks gestation)

Considered at Risk of Preterm Birth (Question 8)

Question 8: Do improvements to the fetus, infant, and child vary by reason women (at less than 30 weeks gestation) considered to be at risk of preterm birth?

At this stage there is insufficient evidence to identify the reasons women were considered at risk of

preterm birth and included in studies relating to the administration of magnesium sulphate.

See Appendix F.8



sulphate for neuroprotection of the fetus, infant or child:

regardless of reason women considered (at less than 30 weeks’ gestation) to be at risk of preterm birth.


B


As for chapter 7.


If triallists collected data on reasons women were considered to be at risk of preterm birth,

these data should be obtained and aggregate analyses conducted.

Individual patient data meta-analysis can be used to explore whether differences in reasons

women were considered to be at risk of preterm birth result in different rates of adverse

outcomes such as cerebral palsy and combined death and cerebral palsy.


Chapter 13: Parity (Question 9)

Question 9: Do improvements to the fetus, infant, and child vary by parity of women?

Parity of women was not reported in any of the trials included in the Doyle 2009 Cochrane review.

At this stage there is insufficient evidence to identify whether parity is a significant factor in the use


See Appendix F.9




regardless of parity (number of previous births for the woman).

*see chapter 8 #

see chapter 9

B


As for Chapter 7.


If triallists collected data on parity, these data should be obtained and aggregate analyses

conducted.

It may be possible to elucidate any influence of parity through individual patient data meta-

analysis.


Chapter 14: Mode of Birth (Question 10)

Question 10: Do improvements to the fetus, infant, and child vary by mode of birth?

This chapter summarises the evidence from the four individual neuroprotective intent trials within

the Doyle 2009 Cochrane review for mode of birth.

Three of the four trials (Crowther 2003, Marret 2006 and Rouse 2008) reported mode of birth

(caesarean section and vaginal birth), but not outcomes for the child by mode of birth.

Mode of birth as an outcome

Overall there was no significant difference in mode of birth between women given magnesium

sulphate and those not given magnesium sulphate. When the three trials are pooled, the results are

non-significant, ranging from a 7% decrease to a 7% increase in the number of caesarean sections

(RR 1.00 95% CI 0.93 to 1.07).

At present there is insufficient evidence to show whether the use of magnesium sulphate has any

influence on the mode of birth.

See Appendix F:10

Table 11: Results of primary outcomes by mode of birth for trials (Doyle 2009 Cochrane Review)

Trial Caesarean Section Vaginal Birth

RR (95% CI)

Crowther 2003

(n=1062 women)

0.98 (0.88 to 1.10) 1.02 (0.90 to 1.17)

Marret 2006

(n=564 women)

1.17 (0.95 to 1.46) 0.91 (0.80 to 1.03)

Rouse 2008

(n=2241 women)

0.97 (0.88 to 1.08) 1.02 (0.95 to 1.09)

OVERALL (n=3867) 1.00 (0.93 to 1.07) 1.00 (0.95 to 1.06)

Mode of birth as an effect modifier

It is possible that the neuroprotective effect of antenatal magnesium sulphate may be modified by

mode of birth. Elective caesarean section has been shown to be associated with reduced neonatal

encephalopathy (Badawi 1998) and there is some suggestion in the literature that caesarean section

may be associated with improved survival and improved neurodevelopmental outcomes for

extremely low birthweight infants (Wilson-Costello 2007).





regardless of anticipated mode of birth.

*see chapter 8 #

see chapter 9

B


As for Chapter 7.


Any modifying effect of mode of birth on neurodevelopmental outcomes could be explored in the

trials included in the Doyle 2009 Cochrane review through a four-way comparison of:

o caesarean births in the magnesium sulphate groups

o caesarean births in the placebo/no treatment groups

o vaginal births in the magnesium sulphate groups

o vaginal births in the placebo/no treatment groups.


Chapter 15: Effect of Antenatal Corticosteroids (Question 11)

Question 11: Do improvements to the fetus, infant, and child vary by combined effect of antenatal corticosteroids and magnesium sulphate?

Table 12: Results of primary outcomes by corticosteroid use for trials (Doyle 2009 Cochrane Review)

Trial High use of antenatal corticosteroids

Crowther 2003 yes

Rouse 2008 yes

Marret 2006 yes

Mittendorf 2002 unknown

At this stage there is insufficient evidence to identify any effect on outcomes when antenatal

corticosteroids have been used.

See Appendix F:11


In women at risk of early preterm* imminent# birth, use magnesium sulphate for neuroprotection of the fetus, infant or child:

whether or not antenatal corticosteroids have been given.


B


As for Chapter 7.


Further data on antenatal corticosteroid use should be obtained from individual triallists and

aggregate analyses conducted.

Individual patient data meta-analysis can be used to explore whether differences in use of

antenatal corticosteroids result in different rates of adverse outcomes such as cerebral palsy

and combined death and cerebral palsy.


References

References to included RCTs

Crowther 2003

a) Crowther CA, Hiller JE, Doyle LW, Haslam RR for the Australasian Collaborative Trial of

Magnesium Sulphate (ACTOMgSO4) Collaborative Group. Effect of magnesium sulfate given for

neuroprotection before preterm birth. JAMA 2003;290(20):2669-76.

b) Crowther CA, Hiller JE, Doyle LW for the ACTOMgSO4 Collaborators Group. Does prenatal

magnesium sulphate reduce the risk of mortality and cerebral palsy in infants born at less than

30 weeks' gestation? - The ACTOMgS04 trial. Perinatal Society of Australia and New Zealand 7th

Annual Congress; 2003 March 9-12; Tasmania, Australia. 2003:A4.

c) Paradisis M, Evans N, Osborn D, Kluckow M, ACTOMgSO4 Collaborators Group. The effect of

antenatal magnesium sulphate on early systemic blood flow in very preterm infants. Pediatric

Research 2004;55 Suppl:114.

d) Smith CA, Crowther CA, Willson K, Hiller JE, Doyle LW. Placental transfer of magnesium

sulphate: a randomised placebo controlled trial. Perinatal Society of Australia and New Zealand

7th Annual Congress; 2003 March 9-12; Tasmania, Australia. 2003:P48.

Marret 2006

a) Marret S, Marpeau L, Zupan-Simunek V, Eurin D, Lévêque C, Hellot MF, et al. Magnesium sulfate

given before very-preterm birth to protect infant brain: the randomized, controlled PREMAG

trial. BJOG: an international journal of obstetrics and gynaecology 2007; Vol. 114, issue 3:310-8.

b) Marret S, Marpeau L, Astruc D, Cambonie G, Follet C, Benichou J. Prenatal magnesium sulfate

(MgSO4) and follow up at two years of age in preterm infants: the randomised controlled

PREMAG trial. Pediatric Academic Societies Annual Meeting; 2007 May 5-8; Toronto, Canada.

c) Marret S, Marpeau L, Benichou J. Benefit of magnesium sulfate given before very preterm birth

to protect infant brain. Pediatrics 2008;121(1):225-6.

d) Marret S, Marpeau L, Follet-Bouhamed C, Cambonie G, Astruc D, Delaporte B, et al. for the

PREMAG Group. Effect of magnesium sulphate on mortality and neurologic morbidity of the

very=preterm newborn with two-year neurological outcome: results of the prospective

PREMAG trial [Effet du sulfate de magnésium sur la mortalité et la morbidité neurologique chez

le prématuré de moins de 33 semaines, avec recul è deux ans: résultats de l'essai prospectif

multicentrique contre placebo PREMAG]. Gynécologie Obstétrique & Fertilité 2008;36:278-88.


e) Marret S, Zupan V, Marpeau L, Adde-Michel C, Benichou J, the Premag Trial Group. Prenatal

magnesium sulphate (MgSO4) and neuroprotection in preterm infants: a randomized controlled

trial. Pediatric Academic Societies Annual Meeting; 2005 May 14-17; Washington DC, USA.

Mittendorf 2002

a) Mittendorf R, Dambrosia J, Pryde PG, Lee KS, Gianopoulos JG, Besinger RE, et al. Association

between the use of antenatal magnesium sulfate in preterm labor and adverse health outcomes

in infants. American Journal of Obstetrics and Gynecology 2002;186(6):1111-8.

b) Mittendorf R, Bentz L, Borg M, Roizen N. Does exposure to antenatal magnesium sulfate

prevent cerebral palsy? American Journal of Obstetrics and Gynecology 2000;182(1 Pt 2):S20.

c) Mittendorf R, Bentz L, Kohn J, Covert R. Use of antenatal magnesium sulfate does not seem to

prevent intraventricular hemorrhage. American Journal of Obstetrics and Gynecology

2000;182(1 Pt 2):S34.

d) Mittendorf R, Besinger R, Santillan M, Gianopoulos J. When used in circumstance of preterm

labor, is there a paradoxical effect of varying exposures to magnesium sulfate (MGSO4) on the

developing human brain? American Journal of Obstetrics and Gynecology 2005;193(6

Suppl):S65.

e) Mittendorf R, Covert R, Boman J, Khoshnood B, Lee KS, Siegler M. Is tocolytic magnesium

sulphate associated with increased total paediatric mortality? Lancet 1997;350(9090):1517-8.

f) Mittendorf R, Covert R, Elin R, Pryde P, Khoshnood B, Sun-Lee K. Umbilical cord serum ionized

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hemorrhage. Journal of Pediatrics 2002;140(5):540-6.

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k) Mittendorf R, Kuban K, Pryde PG, Gianopoulos JG, Yousefzadeh D. Antenatal risk factors

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11.

m) Mittendorf R, Pryde P, Lee KS, Besinger R, Macmillan W, Karlman R, et al. Umbilical cord serum

ionized magnesium levels at delivery are not correlated with neuroprotection in childhood.

American Journal of Obstetrics and Gynecology 2002;187(6 Pt 2):S74.

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staphylococci cultured from the placental chorioamnion space at delivery are associated with

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trial of magnesium sulphate for the prevention of cerebral palsy. Obstetrical & Gynecological

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Appendix A: Process and Methods

Overview of the guideline development process

There was a recognised urgent need for guidelines on the use of magnesium sulphate for

neuroprotection to assist clinical decision making. Since there were no known existing guidelines

suitable for adaptation, a group of experts in their fields met on 17 September 2009 at the University

of Adelaide to discuss developing guidelines. Present at the meeting were Professor Caroline

Crowther, Ms Philippa Middleton, Professor Peter Davis, Associate Professor Vicki Flenady, Dr Lisa

Askie, Dr Helena Oakey, Dr Neil Hotham, Dr Dell Horey and Dr Jane Alsweiler. At this meeting the

group discussed the establishment of a multidisciplinary expert advisory panel to oversee the

development of the guidelines, defined the Panel’s purpose, identified the clinical questions and

harms that needed to be considered and established a process for developing the guidelines.

Establishing the Expert Advisory Panel

A multidisciplinary panel was established to oversee the development of the guidelines.

Representation was invited from:

Health professionals in the fields of maternal fetal medicine, obstetrics, midwifery,

neonatology and neonatal nursing;

Relevant allied health practitioners e.g. pharmacist;

Research methodology experts including epidemiologists and a biostatistician;

Consumer representatives;

Representatives from professional colleges and bodies (RANZCOG; ACM; NZCOM; RACP;

ACNN; and WHA).

Purpose of the Panel

The purpose of the Antenatal Magnesium Sulphate Prior to Preterm Birth for Neuroprotection of the

Fetus, Infant, and Child Guideline Development Panel was to prepare a guideline on best practice for

clinical care on the use of magnesium sulphate prior to preterm birth. The guidelines are relevant for

health professionals who care for women at risk of preterm birth and their babies, pregnant women

and their partners, and policy makers in maternity care.

Clinical Questions Defined

Does the administration of magnesium sulphate to women prior to preterm birth:

Improve the health outcomes for the fetus/infant/child?

Cause adverse outcomes for the women?

Cause adverse outcomes for the fetus/infant/child?

Do any improvements for the fetus/infant/child vary by:

o Gestational age magnesium sulphate given?

o Time magnesium sulphate planned to be given prior to birth?

o Dose regimen planned?

o Number of babies in-utero?

o Reason women considered at risk of preterm birth (preterm labour, preterm

prelabour rupture of the membranes, antepartum haemorrhage, pre-eclampsia, fetal

compromise; maternal factors)?


o Parity of the women?

o Mode of birth?

o Use of antenatal corticosteroids?

Draft Health Outcomes Considered for the Guidelines:

Death and neurosensory disability (including cerebral palsy, blindness, deafness,

developmental delay) for the fetus, infant, and child.

Harmful effects by the therapy for the woman and the child (maternal respiratory

depression, cardiac arrest, hypotension, side effects, and fetal/neonatal side effects.

Resources needed and economic component.

Literature Review Process

It was agreed to follow NHMRC and NZGG guideline processes. There was a systematic identification

and synthesis of the best available scientific evidence. Evidence for effectiveness included systematic

reviews and randomised trials assessing outcomes of antenatal magnesium sulphate for fetal

neuroprotection. In addition, the substantial randomised literature for the use of magnesium

sulphate during pregnancy was assessed for evidence about harms of antenatal magnesium use for

mother and baby. Evidence statements (assessing evidence base, consistency, clinical impact,

generalisability, applicability and draft recommendations) were prepared, and then discussed by the

panel, for each of the clinical questions.

Summary of timeline:

12 Oct 2009 – input sought by email from full panel.

16 Oct 2009 – subsequent drafts discussed by teleconference.

12 Nov 2009 – face to face meeting in Sydney.

19 Dec 2009 – 18 Jan 2010: public consultation of draft guidelines.

12 Dec 2009 – open meeting in Adelaide.

Jan/Feb 2010 – final guideline document.

March 2010 – draft guidelines released.

17 November 2010 – NHMRC approved guidelines.

Appointment of the Panel

On 16 October 2009 the Guideline Panel met via teleconference. Prior to the meeting Panel

members were required to declare their conflict of interest (see p. 52). At the meeting the purpose

of the Panel was established, defined clinical questions were discuss and approved, the NHMRC

evidence statements process used to address these questions was explained and the ongoing process

for developing the guidelines was established.

Development of the Guidelines

Synthesis of new and existing evidence

The Cochrane Library was searched for relevant Cochrane reviews, other systematic reviews and

RCTs (last searched August 2008). PubMed was last searched in August 2008. References of

retrieved articles were checked for potentially relevant studies.


Developing recommendations

The Guideline recommendations for each clinical question were developed using procedures outlined

in the “NHMRC additional levels of evidence and grades for recommendations for developers of

guidelines: Stage 2 consultation 2008 – 2010” (available from the NHMRC website). Each

recommendation was assigned a grade for ‘A’ to ‘D’. ‘A’ refers to a recommendation based on a

body of evidence that can be trusted to guide practice. ‘B’ refers to a recommendation based on a

body of evidence that can be trusted to guide practice in most situations. Grade ‘C’ means that the

body of evidence provides some support for the recommendation, but care should be taken in its

application. Grade ‘D’ means that the body of evidence is weak and the recommendation should be

applied with caution. Each recommendation was assigned a grade taking into account the volume,

consistency, generalisability, applicability and clinical impact of the body of evidence supporting each

recommendation. The standardised evidence statement form used to formulate and grade the

recommendations can be found in Appendix B.

Panel Member Input

Panel members provided input into the draft guideline document on an ongoing basis via email. The

executive group of the Panel met face to face on 12 November 2009 to consider the comments

received from the Panel and to consolidate the draft document. At this meeting the additional

clinical question ‘mode of birth’ was identified.

On 12 December 2009 a workshop was held in Adelaide attended by the Panel members and other

participants with an interest in magnesium sulphate guidelines. The purpose of the meeting was to

provide an overview of the evidence surrounding the use of magnesium sulphate for

neuroprotection, the need for the guidelines, the guideline development process and draft

recommendations, allow participants to provide input into the implementation implications, good

practice points, audit process and further research needed.

Public Consultation Process

The draft Guideline document was released for public consultation in December 2009, published

through The Australian national newspaper and made available on the Australian Research Centre

for Health of Women and Babies (ARCH) website. Public consultation closed on 18 January 2010.

Response to feedback and completion of final guideline document

Material provided through the public consultation process was incorporated into the Guideline

document. A summary of the public consultation comments and Panel member responses are

provided in Appendix I.

Declarations of competing interest of the guideline panel members

Professor Caroline Crowther

Chief Investigator for the Australian Collaborative Trial of Magnesium Sulphate (ACTOMgSO4)

funded through the National Health and Medical Research Council (NHMRC) Project Grant

3503267.

Co-author for the Cochrane Review ‘Magnesium sulphate for preventing preterm birth in

threatened preterm labour’.

Co-author for the Cochrane Review ‘Magnesium sulphate for women at risk of preterm birth

for neuroprotection of the fetus’.

Co-author for the Cochrane Review ‘Magnesium maintenance therapy for preventing

preterm birth after threatened preterm labour’.


Co-author on updates of other Cochrane Reviews assessing antenatal use of magnesium

sulphate.

Professor Lex Doyle



Co-author for the Cochrane Review ‘Magnesium sulphate for preventing preterm birth in

threatened preterm labour’.

Investigator for the ACTOMgSO4 trial.


sulphate.

Professor Lesley McCowan

Assisted in the coordination of the ACTOMgSO4 trial in New Zealand.

Ms Philippa Middleton




sulphate.


Appendix B: How to use the NHMRC Evidence Statement Form

Step 1 — Rate each of the five components

Applying evidence in real clinical situations is not usually straightforward. Consequently guideline

developers find that the body of evidence supporting a recommendation rarely consists of entirely one

rating for all the important components (outlined above). For example, a body of evidence may contain

a large number of studies with a low risk of bias and consistent findings, but which are not directly

applicable to the target population or Australian healthcare context and have only a limited clinical

impact. Alternatively, a body of evidence may only consist of one or two randomised trials with small

sample sizes that have a moderate risk of bias but have a very large clinical impact and are directly

applicable to the Australian healthcare context and target population. The NHMRC evidence grading

system is designed to allow for this mixture of components, while still reflecting the overall body of

evidence supporting a guideline recommendation.

The components described above should be rated according to the matrix shown in Table 1. Enter the

results into the NHMRC Evidence Statement Form (see Appendix C) along with any further notes

relevant to the discussions for each component.

Table 1: Body of evidence matrix

Component A B C D

Excellent Good Satisfactory Poor

Evidence base1 one or more level I

studies with a low risk of bias or several level II studies with a low risk of bias

one or two level II studies with a low risk of bias or a SR/several level III studies with a low risk of bias

one or two level III

studies with a low risk

of bias, or level I or II

studies with a

moderate risk of bias

level IV studies, or

level I to III

studies/SRs with a

high risk of bias

Consistency2 all studies consistent most studies consistent

and inconsistency may

be explained

some inconsistency

reflecting genuine

uncertainty around

clinical question

evidence is

inconsistent

Clinical impact very large substantial moderate slight or restricted

Generalisability population/s studied

in body of evidence

are the same as the

target population for

the guideline

population/s studied in

the body of evidence are

similar to the target

population for the

guideline


body of evidence differ

to target population for

guideline but it is

clinically sensible to

apply this evidence to

target population3


body of evidence differ to

target population and

hard to judge whether it

is sensible to generalise

to target population

Applicability directly applicable to

Australian healthcare

context

applicable to Australian

healthcare context with

few caveats

probably applicable to


context with some

caveats

not applicable to


context

SR = systematic review; several = more than two studies 1 Level of evidence determined from the NHMRC evidence hierarchy – Table 3, Part B

2 If there is only one study, rank this component as ‘not applicable’.

3 For example, results in adults that are clinically sensible to apply to children OR psychosocial outcomes for one cancer that may be applicable to patients with another cancer


The Evidence Statement Form also provides space to enter any other relevant factors that were taken into

account by the guideline developers when judging the body of evidence and developing the wording of the

recommendation.

Step 2 — Prepare an evidence statement matrix

In the ‘Evidence statement matrix ’ section of the form, summarise the guideline developers’ synthesis of

the evidence relating to each component at the right hand side of the form, and fill in the evidence matrix

at the left hand side of the form. Each recommendation should be accompanied by this matrix as well as

the overall grade given to the recommendation (see Step 3). Developers should indicate dissenting

opinions or other relevant issues in the space provided under the evidence matrix.

Step 3 — Formulate a recommendation based on the body of evidence

Develop wording for the recommendation. This should address the specific clinical question and ideally

be written as an action statement. The wording of the recommendation should reflect the strength of

the body of evidence. Words such as ‘must’ or ‘should’ are used when the evidence underpinning the

recommendation is strong, and words such as ‘might’ or ‘could’ are used when the evidence base is

weaker.

Step 4 — Determine the grade for the recommendation

Determine the overall grade of the recommendation based on a summation of the rating for each individual component of the body of evidence. A recommendation cannot be graded A or B unless the evidence base and consistency of the evidence are both rated A or B.

NHMRC overall grades of recommendation are intended to indicate the strength of the body of evidence underpinning the recommendation. This should assist users of the clinical practice guidelines to make appropriate and informed clinical judgments. Grade A or B recommendations are generally based on a body of evidence that can be trusted to guide clinical practice, whereas Grades C or D recommendations must be applied carefully to individual clinical and organisational circumstances and should be interpreted with care (see Table 2).

Table 2: Definition of NHMRC grades of recommendations

Grade of

recommendation

Description

A Body of evidence can be trusted to guide practice

B Body of evidence can be trusted to guide practice in most situations

C Body of evidence provides some support for recommendation(s) but care should be taken in its application

D Body of evidence is weak and recommendation must be applied with caution

Implementing guideline recommendations How the guidelines will be implemented should be considered at the time that the guideline

recommendations are being formulated. Guidelines require an implementation plan that ensures

appropriate roll out, supports and evaluation of guideline effectiveness in improving practice, and

guideline uptake. The Evidence Statement Form asks developers to consider four questions related to

the implementation of each recommendation:

Will this recommendation result in changes in usual care?

Are there any resource implications associated with implementing this recommendation?

Will the implementation of this recommendation require changes in the way care is currently organised?

Are the guideline development group aware of any barriers to the implementation of this recommendation?


Appendix C: NHMRC Evidence Statement Form

(If rating is not completely clear, use the space next to each criteria to note how the group came to a judgment).

Key question(s): Evidence table ref:

1. Evidence base (number of studies, level of evidence and risk of bias in the included studies)

A One or more level I studies with a low risk of bias or several level II studies with

a low risk of bias

B One or two Level II studies with a low risk of bias or SR/several Level III studies

with a low risk of bias

C One or two Level III studies with a low risk of bias or Level I or II studies with a

moderate risk of bias

D Level IV studies or Level I to III studies/SRs with a high risk of bias

2. Consistency (if only one study was available, rank this component as ‘not applicable’)

A All studies consistent

B Most studies consistent and inconsistency can be explained

C Some inconsistency, reflecting genuine uncertainty around question

D Evidence is inconsistent

NA Not applicable (one study only)

3. Clinical impact (Indicate in the space below if the study results varied according to some unknown factor (not simply study quality or sample size) and thus the clinical impact of the

intervention could not be determined)

A Very large

B Substantial

C Moderate

D Slight/Restricted


4. Generalisability (How well does the body of evidence match the population and clinical settings being targeted by the Guideline?)

A Evidence directly generalisable to target population

B Evidence directly generalisable to target population with some caveats

C Evidence not directly generalisable to the target population but could be

sensibly applied

D Evidence not directly generalisable to target population and hard to judge

whether it is sensible to apply

5. Applicability (Is the body of evidence relevant to the Australian healthcare context in terms of health services/delivery of care and cultural factors?)

A Evidence directly applicable to Australian healthcare context

B Evidence applicable to Australian healthcare context with few caveats

C Evidence probably applicable to Australian healthcare context with some

caveats

D Evidence not applicable to Australian healthcare context


Other factors (Indicate here any other factors that you took into account when assessing the evidence base (for example, issues that might cause the group to downgrade or upgrade

the recommendation)

EVIDENCE STATEMENT MATRIX Please summarise the development group’s synthesis of the evidence relating to the key question, taking all the above factors into account.

Component Rating Description

1. Evidence base

2. Consistency

3. Clinical impact

4. Generalisability

5. Applicability

Indicate any dissenting opinions

RECOMMENDATION

What recommendation(s) does the guideline development group draw from this evidence? Use action

statements where possible.

GRADE OF RECOMMENDATION


UNRESOLVED ISSUES

If needed, keep note of specific issues that arise when each recommendation is formulated and that require follow-up.

IMPLEMENTATION OF RECOMMENDATION

Please indicate yes or no to the following questions. Where the answer is yes please provide explanatory information about this. This information will be used to develop the

implementation plan for the guidelines.

Will this recommendation result in changes in usual care? YES

NO

Are there any resource implications associated with implementing this recommendation? YES

NO

Will the implementation of this recommendation require changes in the way care is currently organised? YES

NO


YES

NO


Appendix D: New Zealand Processes

The NZ guiding principles for guideline developers are detailed in the “Handbook for the Preparation of

Explicit Evidence-Based Clinical Practice Guidelines” (NZGG 2001).

ELICIT EVIDENCE-BASED CLINICAL PRACTICE GUIDELINES


Appendix E: Tocolysis Intent and Maternal Neuroprotective Intent

TOCOLYSIS

a) Crowther 2002 compared magnesium sulphate with no magnesium sulphate (either placebo or an

alternative tocolytic drug) for initial (acute) tocolysis in women thought to be in preterm labour.

This Cochrane review included 23 trials (with over 2000 women). The last search was conducted in

May 2002.

Magnesium sulphate was found to be ineffective at either delaying birth or preventing preterm birth,

and its use was associated with increased mortality for infants (of the 24 deaths (18 in the magnesium

group and 10 in the placebo group), all but two were neonates or infants).

Cochrane review of magnesium sulphate for tocolysis (Crowther 2002)

TOCOLYSIS RR (95% CI) Number of trials, participants

Birth within 48 hours of tocolysis 0.85 (0.58 to 1.25) 11 trials, 881 women

Preterm birth (< 37 weeks) 0.91 (0.75 to 1.11) 6 trials, 424 women

Perinatal mortality 2.82 (1.20 to 6.62) 7 trials, 727 infants

b) Crowther 1998 compared magnesium sulphate with no magnesium sulphate (either a placebo or an

alternative drug) used for maintenance in women who already had been given some medication to

stop early labour. The Cochrane review included three trials (303 women, 322 infants). The last

search for this review was conducted in August 2002.

No differences in the incidence of preterm birth or perinatal mortality were seen when magnesium

sulphate maintenance therapy was compared with either a placebo, or no treatment, or alternative

therapies (ritodrine or terbutaline).

Cochrane review of magnesium sulphate for maintenance of tocolysis (Crowther 1998)

TOCOLYSIS (MAINTENANCE) RR (95% CI) Number of trials, participants

Preterm birth < 37 weeks (magnesium v placebo/no treatment)

0.85 (0.47 to 1.51) 1 trial, 50 infants

Preterm birth < 37 weeks (magnesium v ritodrine or terbutaline)

0.98 (0.56 to 1.72) 2 trials, 100 infants

Perinatal mortality (magnesium v placebo/no treatment)

5.00 (0.25 to 99.16) 1 trial, 50 infants

Perinatal mortality (magnesium v ritodrine or terbutaline)

5.00 (0.25 to 99.16) 1 trial, 50 infants

Summary of evidence statement judgements for tocolysis

The evidence base for tocolysis was of poor to moderate quality (high to moderate risk of bias), with

some inconsistency between the results of different trials. Tocolysis with magnesium sulphate was

judged to have a substantial negative impact on outcomes, in particular, increased infant mortality. The

evidence was judged to be both generalisable and applicable.


NEUROPROTECTION (MOTHER) – PRE-ECLAMPSIA

Magnesium sulphate is given to pregnant women with the intention of preventing eclampsia.

Duley 2003 compared magnesium sulphate with placebo or no anticonvulsant for preventing eclampsia

in women with pre-eclampsia. This Cochrane review included 11,444 women (six trials) and 9961

infants (three trials). The last search was conducted in November 2002.

Duley 2003 found that while magnesium sulphate more than halved the risk of eclampsia, and probably

reduced the risk of maternal death, the review did not demonstrate effects on improved infant

outcomes. However, there was no overall difference in the risk of stillbirth or neonatal death (RR 1.04,

95% CI 0.93 to 1.15) or other infant outcomes. This was also true for the subset of unpublished

outcome data provided by the trial investigators for the Doyle 2009 Cochrane review.

Summary of evidence statement judgements for maternal neuroprotection

The evidence base for maternal neuroprotection (preventing pre-eclampsia) with magnesium sulphate

has a mixed risk of bias and results are fairly consistent between trials. The impact on fetal and infant

outcomes was judged to be negligible. While the evidence may be applicable, it has lower

generalisability as most women in the largest trial were from low or middle income countries.


Q1-Q3: Effectiveness Summary for Cochrane Reviews

Tocolysis

Crowther 2002

This Cochrane review included 23 trials (with over 2000 women). Magnesium sulphate was ineffective at

delaying birth or preventing preterm birth, and its use is associated with an increased mortality for the

infant.

DEATH

Crowther 1998 This Cochrane review included three trials (303 women) and no differences in the incidence of preterm

birth or perinatal mortality were seen when magnesium sulphate maintenance therapy was compared with

placebo or no treatment (2 trials (n=183 women); or alternative therapies (ritodrine or terbutaline).

DEATH

Study or Subgroup

Beall 1985

Cotton 1984

Cox 1990

Fox 1993

Glock 1993

Mittendorf 1997

Morales 1993

Total (95% CI)

Total events

Heterogeneity: Chi² = 5.89, df = 4 (P = 0.21); I² = 32%

Test for overall effect: Z = 2.38 (P = 0.02)

Events

0

1

8

0

0

8

1

18

Total

46

16

78

45

41

55

59

340

Events

0

1

2

0

2

0

1

6

Total

85

19

89

45

39

52

58

387

Weight

13.3%

27.2%

37.3%

7.5%

14.7%

100.0%

M-H, Fixed, 95% CI

Not estimable

1.19 [0.08, 17.51]

4.56 [1.00, 20.86]

Not estimable

0.19 [0.01, 3.85]

16.09 [0.95, 271.91]

0.98 [0.06, 15.35]

2.82 [1.20, 6.62]

Magnesium No magnesium Risk Ratio Risk Ratio

M-H, Fixed, 95% CI

0.002 0.1 1 10 500

Favours magnesium Favours no magnesium

Study or Subgroup

10.1.1 Stillbirth

Subtotal (95% CI)

Total events

Heterogeneity: Not applicable

Test for overall effect: Not applicable

10.1.2 Death before discharge among live-born infants

Ricci 1991

Subtotal (95% CI)

Total events



Total (95% CI)

Total events



Test for subgroup differences: Not applicable

Events

0

2

2

2

Total

0

25

25

25

Events

0

0

0

0

Total

0

25

25

25

Weight

100.0%

100.0%

100.0%

M-H, Fixed, 95% CI

Not estimable

5.00 [0.25, 99.16]

5.00 [0.25, 99.16]

5.00 [0.25, 99.16]


M-H, Fixed, 95% CI

0.01 0.1 1 10 100



Neuroprotection (Mother) – Pre-eclampsia

Duley 2003

This Cochrane review compared magnesium sulphate with placebo or no anticonvulsant for preventing eclampsia in women with pre-eclampsia. This review included 11,444 women (six trials) and 9961 infants (three trials) and found that magnesium sulphate more than halves the risk of eclampsia, and probably reduces the risk of maternal death. It does not influence short-term outcomes for the baby.

DEATH

Study or Subgroup

9.1.1 Stillbirth

South Africa 1994

South Africa 1998

Magpie 2002

Subtotal (95% CI)

Total events



9.1.2 Perinatal death

South Africa 1994

Magpie 2002

Subtotal (95% CI)

Total events



9.1.3 Neonatal death

Magpie 2002

Subtotal (95% CI)

Total events



9.1.4 Infant death (from 28 days to 1 year)

Magpie 2002

Subtotal (95% CI)

Total events



Total (95% CI)

Total events



Test for subgroup differences: Not applicable

Events

13

38

373

424

20

518

538

187

187

16

16

1165

Total

117

348

4538

5003

117

4538

4655

4162

4162

4162

4162

17982

Events

14

28

384

426

25

516

541

159

159

15

15

1141

Total

118

354

4486

4958

118

4486

4604

4098

4098

4098

4098

17758

Weight

1.2%

2.4%

33.7%

37.3%

2.2%

45.2%

47.4%

14.0%

14.0%

1.3%

1.3%

100.0%

M-H, Fixed, 95% CI

0.94 [0.46, 1.91]

1.38 [0.87, 2.20]

0.96 [0.84, 1.10]

0.99 [0.87, 1.12]

0.81 [0.48, 1.37]

0.99 [0.88, 1.11]

0.98 [0.88, 1.10]

1.16 [0.94, 1.42]

1.16 [0.94, 1.42]

1.05 [0.52, 2.12]

1.05 [0.52, 2.12]

1.01 [0.93, 1.09]

Magnesium No Magnesium Risk Ratio Risk Ratio

M-H, Fixed, 95% CI

0.2 0.5 1 2 5



Appendix F: Evidence Statements and Tables – Questions 1 to 11

Q1 – Q3: Effectiveness Summary For Cochrane Reviews

NHMRC Evidence Statement

Key question(s):

Q1: Does the administration of magnesium sulphate to women prior to preterm birth improve health outcomes for the fetus/infant/child?

Q2: Does the use of magnesium sulphate prior to preterm birth cause adverse outcome for women?

Q3: Does the use of magnesium sulphate prior to preterm birth cause adverse outcome for the fetus/infant/child?

1. Evidence base

NEUROPROTECTIVE INTENT Four RCTs (level ll intervention), generally with a low risk of bias, included in a systematic review (level I).

A (One or more Level I studies with a low risk of bias or several Level ll

studies with low risk of bias)

2. Consistency

There was some inconsistency between studies, which can probably mostly be explained (different regimens used in each of the four studies).

B (Most studies consistent and

inconsistency can be explained)

3. Clinical Impact

Neuroprotection and prevention of cerebral palsy in this vulnerable preterm population will have a very large potential impact.

The number of women needed to be treated to benefit one baby by avoiding cerebral palsy is 63 (95% confidence interval 44 to 155).

Women given magnesium sulphate were about three times more likely to cease therapy compared with women not given magnesium therapy mainly due to flushing, nausea/vomiting and headaches. Hypotension and respiratory depression were also increased with magnesium use.

No harms for the fetus, infant or child were significantly increased with antenatal use of magnesium.

A (very large)

4. Generalisability

One neuroprotective trial was conducted in Australia and New Zealand and most of the other trials had populations and settings directly generalisable to the target population (Australian women at risk of preterm birth); women in the large Rouse trial represented a narrower population (87% with PPROM).

B (Evidence directly generalisable to

target population with some caveats)

5. Applicability

Magnesium sulphate is already available in Australian and New Zealand maternity settings and therefore this evidence is directly applicable to the Australian health care context.

A (Evidence directly applicable to Australian healthcare context)

EVIDENCE STATEMENT MATRIX

Component Rating

Evidence base A

Consistency B

Clinical impact A

Generalisability B


Applicability A

RECOMMENDATION


sulphate for neuroprotection of the fetus, infant and child:

*when gestational age is less than 30 weeks. #when very preterm birth is planned or definitely expected within 24

hours. (When birth is planned, commence magnesium sulphate as close

to four hours before birth as possible).

A

UNRESOLVED ISSUES

See subsequent chapters


Will this recommendation result in changes in usual care?

Partially – some obstetric settings are already using magnesium sulphate for this indication.

YES


Yes, setting up, maintaining and monitoring magnesium infusions will incur extra staff time.

(On the other hand, at an overall societal and health systems level, fewer cases of cerebral palsy will mean cost savings).

YES


Partially, midwifery/nursing staff will require extra time to manage the magnesium infusions.

YES


Yes, as above – extra time required, plus additional task in the busy and perhaps fraught setting of a preterm birth.

YES


Appendix F: Evidence Tables and Graphs: Q1-3: OVERALL

Doyle 2009

DEATH

CEREBRAL PALSY

DEATH OR CEREBRAL PALSY

Study or Subgroup

Crowther 2003

Marret 2006

Mittendorf 2002

Rouse 2008

Total (95% CI)

Total events



Events

87

34

2

103

226

Total

629

352

30

1188

2199

Events

107

38

1

96

242

Total

626

336

29

1256

2247

Weight

44.6%

16.2%

0.4%

38.8%

100.0%

M-H, Fixed, 95% CI

0.81 [0.62, 1.05]

0.85 [0.55, 1.32]

1.93 [0.19, 20.18]

1.13 [0.87, 1.48]

0.95 [0.80, 1.12]


M-H, Fixed, 95% CI

0.05 0.2 1 5 20


Study or Subgroup

Crowther 2003

Marret 2006

Mittendorf 2002

Rouse 2008

Total (95% CI)

Total events



Events

36

22

3

41

102

Total

629

352

30

1188

2199

Events

42

30

0

74

146

Total

626

336

29

1256

2247

Weight

29.0%

21.1%

0.3%

49.5%

100.0%

M-H, Fixed, 95% CI

0.85 [0.55, 1.31]

0.70 [0.41, 1.19]

6.77 [0.37, 125.65]

0.59 [0.40, 0.85]

0.71 [0.55, 0.91]


M-H, Fixed, 95% CI

0.001 0.1 1 10 1000


Study or Subgroup

Crowther 2003

Marret 2006

Mittendorf 2002

Rouse 2008

Total (95% CI)

Total events

Heterogeneity: Tau² = 0.00; Chi² = 3.17, df = 3 (P = 0.37); I² = 5%


Events

123

56

5

144

328

Total

629

352

30

1188

2199

Events

149

67

1

170

387

Total

626

336

29

1256

2247

Weight

39.9%

18.2%

0.5%

41.4%

100.0%

M-H, Random, 95% CI

0.82 [0.66, 1.02]

0.80 [0.58, 1.10]

4.83 [0.60, 38.90]

0.90 [0.73, 1.10]

0.85 [0.74, 0.98]


M-H, Random, 95% CI

0.02 0.1 1 10 50



F: Q1-3: OVERALL

SUBSTANTIAL GROSS MOTOR DYSFUNCTION

DEATH OR SUBSTANTIAL MOTOR DYSFUNCTION

ANY NEUROLOGICAL IMPAIRMENT

DEVELOPMENT DELAY OR INTELLECTUAL IMPAIRMENT

Study or Subgroup

Crowther 2003

Marret 2006

Rouse 2008

Total (95% CI)

Total events



Events

18

18

20

56

Total

629

352

1188

2169

Events

34

22

38

94

Total

626

336

1256

2218

Weight

36.4%

24.1%

39.5%

100.0%

M-H, Fixed, 95% CI

0.53 [0.30, 0.92]

0.78 [0.43, 1.43]

0.56 [0.33, 0.95]

0.60 [0.43, 0.83]


M-H, Fixed, 95% CI

0.01 0.1 1 10 100


Study or Subgroup

Crowther 2003

Marret 2006

Rouse 2008

Total (95% CI)

Total events



Events

105

52

123

280

Total

629

352

1188

2169

Events

141

60

134

335

Total

626

336

1256

2218

Weight

39.8%

21.4%

38.8%

100.0%

M-H, Random, 95% CI

0.74 [0.59, 0.93]

0.83 [0.59, 1.16]

0.97 [0.77, 1.22]

0.84 [0.71, 1.00]


M-H, Random, 95% CI

0.1 0.2 0.5 1 2 5 10


Study or Subgroup

Crowther 2003

Total (95% CI)

Total events



Events

193

193

Total

629

629

Events

187

187

Total

626

626

Weight

100.0%

100.0%

M-H, Fixed, 95% CI

1.03 [0.87, 1.21]

1.03 [0.87, 1.21]


M-H, Fixed, 95% CI

0.1 0.2 0.5 1 2 5 10


Study or Subgroup

Crowther 2003

Marret 2006

Rouse 2008

Total (95% CI)

Total events



Events

176

57

406

639

Total

629

352

1188

2169

Events

170

63

427

660

Total

626

336

1256

2218

Weight

26.2%

9.9%

63.9%

100.0%

M-H, Fixed, 95% CI

1.03 [0.86, 1.23]

0.86 [0.62, 1.20]

1.01 [0.90, 1.12]

1.00 [0.91, 1.09]


M-H, Fixed, 95% CI

0.5 0.7 1 1.5 2



F: Q1-3: OVERALL

MAJOR NEUROLOGICAL DISABILITY

INTRAVENTRICULAR HAEMORRHAGE

INTRAVENTRICULAR HAEMORRHAGE (grade 3/4)

PERIVENTRICULAR LEUKOMALACIA

Study or Subgroup

Crowther 2003

Total (95% CI)

Total events



Events

89

89

Total

629

629

Events

78

78

Total

626

626

Weight

100.0%

100.0%

M-H, Fixed, 95% CI

1.14 [0.86, 1.51]

1.14 [0.86, 1.51]


M-H, Fixed, 95% CI

0.1 0.2 0.5 1 2 5 10


Study or Subgroup

Crowther 2003

Marret 2006

Mittendorf 2002

Rouse 2008

Total (95% CI)

Total events



Events

165

71

13

218

467

Total

629

352

85

1188

2254

Events

148

82

11

252

493

Total

626

336

80

1256

2298

Weight

30.4%

17.2%

2.3%

50.1%

100.0%

M-H, Fixed, 95% CI

1.11 [0.92, 1.34]

0.83 [0.62, 1.09]

1.11 [0.53, 2.34]

0.91 [0.78, 1.08]

0.96 [0.86, 1.08]


M-H, Fixed, 95% CI

0.5 0.7 1 1.5 2


Study or Subgroup

Crowther 2003

Rouse 2008

Total (95% CI)

Total events



Events

49

23

72

Total

629

1188

1817

Events

50

38

88

Total

626

1256

1882

Weight

57.6%

42.4%

100.0%

M-H, Fixed, 95% CI

0.98 [0.67, 1.42]

0.64 [0.38, 1.07]

0.83 [0.62, 1.13]


M-H, Fixed, 95% CI

0.2 0.5 1 2 5


Study or Subgroup

Crowther 2003

Marret 2006

Mittendorf 2002

Rouse 2008

Total (95% CI)

Total events



Events

22

27

1

21

71

Total

629

352

85

1188

2254

Events

21

28

0

27

76

Total

626

336

80

1256

2298

Weight

27.5%

37.5%

0.7%

34.3%

100.0%

M-H, Fixed, 95% CI

1.04 [0.58, 1.88]

0.92 [0.55, 1.53]

2.83 [0.12, 68.37]

0.82 [0.47, 1.45]

0.93 [0.68, 1.28]


M-H, Fixed, 95% CI

0.01 0.1 1 10 100



F: Q1-3: OVERALL

BLINDNESS

DEAFNESS

Study or Subgroup

Crowther 2003

Marret 2006

Total (95% CI)

Total events



Events

1

1

2

Total

629

352

981

Events

1

1

2

Total

626

336

962

Weight

49.5%

50.5%

100.0%

M-H, Fixed, 95% CI

1.00 [0.06, 15.88]

0.95 [0.06, 15.20]

0.97 [0.14, 6.90]


M-H, Fixed, 95% CI

0.01 0.1 1 10 100


Study or Subgroup

Crowther 2003

Marret 2006

Total (95% CI)

Total events



Events

8

0

8

Total

629

352

981

Events

7

4

11

Total

626

336

962

Weight

66.2%

33.8%

100.0%

M-H, Random, 95% CI

1.14 [0.41, 3.12]

0.11 [0.01, 1.96]

0.51 [0.05, 4.96]


M-H, Random, 95% CI

0.005 0.1 1 10 200



Q4: Gestational Age


Key question(s):

Q4: Do improvements to the fetus/infant/child vary by gestational age magnesium sulphate given?

1. Evidence base

Subgroup analysis from 4 RCTs with low risk of bias; therefore the comparisons by gestational age are non-randomised comparisons (level III).

B (Several Level lll studies with

low risk of bias)

2. Consistency



3. Clinical Impact

Overall impact is very large. A (overall)

4. Generalisability

As for overall; women in the large Rouse trial represented a narrower population (87% with PPROM).

B (Evidence directly

generalisable to target population with some

caveats)

5. Applicability

As for overall A (Evidence directly applicable

to Australian healthcare context)

Other factors

In the absence of being able to distinguish different levels of clinical impact between the present gestational age subgroups, the choices are to:

a) make no recommendation regarding gestational age; b) make a recommendation that magnesium sulphate can be given up to 34 weeks; c) make a recommendation that magnesium sulphate be only given to women less than 32 weeks; d) make a recommendation that magnesium sulphate be only given to women less than 30 weeks

gestation.


Component Rating

Evidence base B

Consistency B

Clinical impact A (overall)

Generalisability B

Applicability A


RECOMMENDATION

Magnesium sulphate be only given to women less than 30 weeks gestation.

B

UNRESOLVED ISSUES

Some of the trials have stratified by gestational age but have not published these analyses.

Individual patient data meta-analyses by gestational age are needed.




YES


YES


YES


Appendix F 4: Evidence Table and Graphs: GESTATIONAL AGE

Study Gestational age

Mittendorf 2002 < 34 weeks at randomisation

Marret 2006 < 33 weeks

Rouse 2008 < 32 weeks

Crowther 2003 < 30 weeks

DEATH

Study or Subgroup

11.1.1 < 34 weeks at randomisation

Mittendorf 2002

Subtotal (95% CI)

Total events




Marret 2006

Subtotal (95% CI)

Total events




Rouse 2008

Subtotal (95% CI)

Total events




Crowther 2003

Subtotal (95% CI)

Total events



Total (95% CI)

Total events



Events

2

2

34

34

103

103

87

87

226

Total

30

30

352

352

1188

1188

629

629

2199

Events

1

1

38

38

96

96

107

107

242

Total

29

29

336

336

1256

1256

626

626

2247

Weight

0.4%

0.4%

16.2%

16.2%

38.8%

38.8%

44.6%

44.6%

100.0%

M-H, Fixed, 95% CI

1.93 [0.19, 20.18]

1.93 [0.19, 20.18]

0.85 [0.55, 1.32]

0.85 [0.55, 1.32]

1.13 [0.87, 1.48]

1.13 [0.87, 1.48]

0.81 [0.62, 1.05]

0.81 [0.62, 1.05]

0.95 [0.80, 1.12]

Favours magnesium No magnesium Risk Ratio Risk Ratio

M-H, Fixed, 95% CI

0.05 0.2 1 5 20



F 4: GESTATIONAL AGE

CEREBRAL PALSY

Study or Subgroup


Mittendorf 2002

Subtotal (95% CI)

Total events




Marret 2006

Subtotal (95% CI)

Total events




Rouse 2008

Subtotal (95% CI)

Total events




Crowther 2003

Subtotal (95% CI)

Total events



Total (95% CI)

Total events



Events

3

3

22

22

41

41

36

36

102

Total

30

30

352

352

1188

1188

629

629

2199

Events

0

0

30

30

74

74

42

42

146

Total

29

29

336

336

1256

1256

626

626

2247

Weight

0.3%

0.3%

21.1%

21.1%

49.5%

49.5%

29.0%

29.0%

100.0%

M-H, Fixed, 95% CI

6.77 [0.37, 125.65]

6.77 [0.37, 125.65]

0.70 [0.41, 1.19]

0.70 [0.41, 1.19]

0.59 [0.40, 0.85]

0.59 [0.40, 0.85]

0.85 [0.55, 1.31]

0.85 [0.55, 1.31]

0.71 [0.55, 0.91]


M-H, Fixed, 95% CI

0.01 0.1 1 10 100





Study or Subgroup


Mittendorf 2002

Subtotal (95% CI)

Total events




Marret 2006

Subtotal (95% CI)

Total events




Rouse 2008

Subtotal (95% CI)

Total events




Crowther 2003

Subtotal (95% CI)

Total events



Total (95% CI)

Total events



Events

5

5

56

56

144

144

123

123

328

Total

30

30

352

352

1188

1188

629

629

2199

Events

1

1

67

67

170

170

149

149

387

Total

29

29

336

336

1256

1256

626

626

2247

Weight

0.5%

0.5%

18.2%

18.2%

41.4%

41.4%

39.9%

39.9%

100.0%

M-H, Random, 95% CI

4.83 [0.60, 38.90]

4.83 [0.60, 38.90]

0.80 [0.58, 1.10]

0.80 [0.58, 1.10]

0.90 [0.73, 1.10]

0.90 [0.73, 1.10]

0.82 [0.66, 1.02]

0.82 [0.66, 1.02]

0.85 [0.74, 0.98]


M-H, Random, 95% CI

0.05 0.2 1 5 20





Study or Subgroup


Subtotal (95% CI)

Total events




Marret 2006

Subtotal (95% CI)

Total events




Rouse 2008

Subtotal (95% CI)

Total events




Crowther 2003

Subtotal (95% CI)

Total events



Total (95% CI)

Total events



Events

0

18

18

20

20

18

18

56

Total

0

352

352

1188

1188

629

629

2169

Events

0

22

22

38

38

34

34

94

Total

0

336

336

1256

1256

626

626

2218

Weight

24.1%

24.1%

39.5%

39.5%

36.4%

36.4%

100.0%

M-H, Fixed, 95% CI

Not estimable

0.78 [0.43, 1.43]

0.78 [0.43, 1.43]

0.56 [0.33, 0.95]

0.56 [0.33, 0.95]

0.53 [0.30, 0.92]

0.53 [0.30, 0.92]

0.60 [0.43, 0.83]


M-H, Fixed, 95% CI

0.2 0.5 1 2 5





Study or Subgroup


Subtotal (95% CI)

Total events




Marret 2006

Subtotal (95% CI)

Total events




Rouse 2008

Subtotal (95% CI)

Total events




Crowther 2003

Subtotal (95% CI)

Total events



Total (95% CI)

Total events



Events

0

52

52

123

123

105

105

280

Total

0

352

352

1188

1188

629

629

2169

Events

0

60

60

134

134

141

141

335

Total

0

336

336

1256

1256

626

626

2218

Weight

21.4%

21.4%

38.8%

38.8%

39.8%

39.8%

100.0%

M-H, Random, 95% CI

Not estimable

0.83 [0.59, 1.16]

0.83 [0.59, 1.16]

0.97 [0.77, 1.22]

0.97 [0.77, 1.22]

0.74 [0.59, 0.93]

0.74 [0.59, 0.93]

0.84 [0.71, 1.00]


M-H, Random, 95% CI

0.5 0.7 1 1.5 2





Study or Subgroup


Subtotal (95% CI)

Total events




Subtotal (95% CI)

Total events




Subtotal (95% CI)

Total events




Crowther 2003

Subtotal (95% CI)

Total events



Events

0

0

0

193

193

Total

0

0

0

629

629

Events

0

0

0

187

187

Total

0

0

0

626

626

Weight

100.0%

100.0%

M-H, Fixed, 95% CI

Not estimable

Not estimable

Not estimable

1.03 [0.87, 1.21]

1.03 [0.87, 1.21]


M-H, Fixed, 95% CI

0.5 0.7 1 1.5 2





Study or Subgroup


Subtotal (95% CI)

Total events




Marret 2006

Subtotal (95% CI)

Total events




Rouse 2008

Subtotal (95% CI)

Total events




Crowther 2003

Subtotal (95% CI)

Total events



Total (95% CI)

Total events



Events

0

57

57

406

406

176

176

639

Total

0

352

352

1188

1188

629

629

2169

Events

0

63

63

427

427

170

170

660

Total

0

336

336

1256

1256

626

626

2218

Weight

9.9%

9.9%

63.9%

63.9%

26.2%

26.2%

100.0%

M-H, Fixed, 95% CI

Not estimable

0.86 [0.62, 1.20]

0.86 [0.62, 1.20]

1.01 [0.90, 1.12]

1.01 [0.90, 1.12]

1.03 [0.86, 1.23]

1.03 [0.86, 1.23]

1.00 [0.91, 1.09]


M-H, Fixed, 95% CI

0.5 0.7 1 1.5 2





Study or Subgroup


Subtotal (95% CI)

Total events




Subtotal (95% CI)

Total events




Subtotal (95% CI)

Total events




Crowther 2003

Subtotal (95% CI)

Total events



Events

0

0

0

89

89

Total

0

0

0

629

629

Events

0

0

0

78

78

Total

0

0

0

626

626

Weight

100.0%

100.0%

M-H, Fixed, 95% CI

Not estimable

Not estimable

Not estimable

1.14 [0.86, 1.51]

1.14 [0.86, 1.51]


M-H, Fixed, 95% CI

0.1 0.2 0.5 1 2 5 10





Study or Subgroup


Mittendorf 2002

Subtotal (95% CI)

Total events




Marret 2006

Subtotal (95% CI)

Total events




Rouse 2008

Subtotal (95% CI)

Total events




Crowther 2003

Subtotal (95% CI)

Total events



Total (95% CI)

Total events



Events

13

13

71

71

218

218

165

165

467

Total

85

85

352

352

1188

1188

629

629

2254

Events

11

11

82

82

252

252

148

148

493

Total

80

80

336

336

1256

1256

626

626

2298

Weight

2.3%

2.3%

17.2%

17.2%

50.1%

50.1%

30.4%

30.4%

100.0%

M-H, Fixed, 95% CI

1.11 [0.53, 2.34]

1.11 [0.53, 2.34]

0.83 [0.62, 1.09]

0.83 [0.62, 1.09]

0.91 [0.78, 1.08]

0.91 [0.78, 1.08]

1.11 [0.92, 1.34]

1.11 [0.92, 1.34]

0.96 [0.86, 1.08]


M-H, Fixed, 95% CI

0.5 0.7 1 1.5 2





Study or Subgroup


Subtotal (95% CI)

Total events




Subtotal (95% CI)

Total events




Rouse 2008

Subtotal (95% CI)

Total events




Crowther 2003

Subtotal (95% CI)

Total events



Total (95% CI)

Total events



Events

0

0

23

23

49

49

72

Total

0

0

1188

1188

629

629

1817

Events

0

0

38

38

50

50

88

Total

0

0

1256

1256

626

626

1882

Weight

42.4%

42.4%

57.6%

57.6%

100.0%

M-H, Fixed, 95% CI

Not estimable

Not estimable

0.64 [0.38, 1.07]

0.64 [0.38, 1.07]

0.98 [0.67, 1.42]

0.98 [0.67, 1.42]

0.83 [0.62, 1.13]


M-H, Fixed, 95% CI

0.2 0.5 1 2 5





Study or Subgroup


Mittendorf 2002

Subtotal (95% CI)

Total events




Marret 2006

Subtotal (95% CI)

Total events




Rouse 2008

Subtotal (95% CI)

Total events




Crowther 2003

Subtotal (95% CI)

Total events



Total (95% CI)

Total events



Events

1

1

27

27

21

21

22

22

71

Total

85

85

352

352

1188

1188

629

629

2254

Events

0

0

28

28

27

27

21

21

76

Total

80

80

336

336

1256

1256

626

626

2298

Weight

0.7%

0.7%

37.5%

37.5%

34.3%

34.3%

27.5%

27.5%

100.0%

M-H, Fixed, 95% CI

2.83 [0.12, 68.37]

2.83 [0.12, 68.37]

0.92 [0.55, 1.53]

0.92 [0.55, 1.53]

0.82 [0.47, 1.45]

0.82 [0.47, 1.45]

1.04 [0.58, 1.88]

1.04 [0.58, 1.88]

0.93 [0.68, 1.28]


M-H, Fixed, 95% CI

0.01 0.1 1 10 100




BLINDNESS

Study or Subgroup


Subtotal (95% CI)

Total events




Marret 2006

Subtotal (95% CI)

Total events




Subtotal (95% CI)

Total events




Crowther 2003

Subtotal (95% CI)

Total events



Total (95% CI)

Total events



Events

0

1

1

0

1

1

2

Total

0

352

352

0

629

629

981

Events

0

1

1

0

1

1

2

Total

0

336

336

0

626

626

962

Weight

50.5%

50.5%

49.5%

49.5%

100.0%

M-H, Fixed, 95% CI

Not estimable

0.95 [0.06, 15.20]

0.95 [0.06, 15.20]

Not estimable

1.00 [0.06, 15.88]

1.00 [0.06, 15.88]

0.97 [0.14, 6.90]


M-H, Fixed, 95% CI

0.05 0.2 1 5 20




DEAFNESS

Study or Subgroup


Subtotal (95% CI)

Total events




Marret 2006

Subtotal (95% CI)

Total events




Subtotal (95% CI)

Total events




Crowther 2003

Subtotal (95% CI)

Total events



Total (95% CI)

Total events



Events

0

0

0

0

8

8

8

Total

0

352

352

0

629

629

981

Events

0

4

4

0

7

7

11

Total

0

336

336

0

626

626

962

Weight

33.8%

33.8%

66.2%

66.2%

100.0%

M-H, Random, 95% CI

Not estimable

0.11 [0.01, 1.96]

0.11 [0.01, 1.96]

Not estimable

1.14 [0.41, 3.12]

1.14 [0.41, 3.12]

0.51 [0.05, 4.96]


M-H, Random, 95% CI

0.005 0.1 1 10 200



Q5: Time Magnesium Sulphate Planned To Be Given Prior To Preterm Birth


Key question(s):

Q5: Do improvements to the fetus/infant/child vary by time magnesium sulphate planned to be given prior to preterm birth?

1. Evidence base

Subgroup analysis from four RCTs with low risk of bias; therefore some of the comparisons by time magnesium is planned are non-randomised comparisons (level III).

B (Several Level II and lll studies

with low risk of bias)

2. Consistency



3. Clinical Impact

Overall impact is very large A (overall)

4. Generalisability

B overall; but A for the birth planned within 24 hours subgroup A (Evidence directly


caveats)

5. Applicability

As for overall A (Evidence directly applicable

to Australian healthcare context)

Other factors

In the absence of being able to assess clinical impact, the choices are:

a) To make no recommendation regarding the timing of administration of magnesium; b) To make a recommendation that magnesium sulphate be only given to women where birth is planned

or expected within 24 hours; c) To make a recommendation that magnesium sulphate be given where birth is definitely expected

within 24 hours, ideally within 4 hours of a planned birth.


Component Rating

Evidence base B

Consistency B


Generalisability A

Applicability A


RECOMMENDATION

In women at risk of early preterm* imminent# birth, use magnesium sulphate for neuroprotection of the fetus, infant and child:

o When early preterm birth is planned or definitely expected within 24 hours. (When birth is planned, commence magnesium sulphate as close to four hours before birth as possible).

*when gestational age is less than 30 weeks

#when early preterm birth is planned or definitely expected within 24 hours.

A

UNRESOLVED ISSUES

Need to try to get more detailed timings from trials.

Individual patient data meta-analysis needed.




YES


YES


YES


Appendix F 5: Evidence table and Graphs: TIMING

Study Timing

Crowther 2003,

Marret 2006

Where birth was planned or expected within 24 hours

Rouse 2008 Where birth was planned or expected within 24 hours for indicated preterm birth (3.1% only); otherwise advanced preterm labour, with cervical dilatation between 4 and 8 cm (10.3%); PPROM 86.7% - median 25 hours, interquartile range 11 to 63 hours from rupture)

Mittendorf 2002 Not specified

DEATH

Study or Subgroup

12.1.1 within 24 hours

Crowther 2003

Marret 2006

Subtotal (95% CI)

Total events



12.1.2 up to 63 hours

Rouse 2008

Subtotal (95% CI)

Total events



12.1.3 not specified

Mittendorf 2002

Subtotal (95% CI)

Total events



Total (95% CI)

Total events



Events

87

34

121

103

103

2

2

226

Total

629

352

981

1188

1188

30

30

2199

Events

107

38

145

96

96

1

1

242

Total

626

336

962

1256

1256

29

29

2247

Weight

44.6%

16.2%

60.8%

38.8%

38.8%

0.4%

0.4%

100.0%

M-H, Fixed, 95% CI

0.81 [0.62, 1.05]

0.85 [0.55, 1.32]

0.82 [0.66, 1.03]

1.13 [0.87, 1.48]

1.13 [0.87, 1.48]

1.93 [0.19, 20.18]

1.93 [0.19, 20.18]

0.95 [0.80, 1.12]


M-H, Fixed, 95% CI

0.05 0.2 1 5 20



F 5: TIMING

CEREBRAL PALSY


Study or Subgroup


Crowther 2003

Marret 2006

Subtotal (95% CI)

Total events




Rouse 2008

Subtotal (95% CI)

Total events




Mittendorf 2002

Subtotal (95% CI)

Total events



Total (95% CI)

Total events



Events

36

22

58

41

41

3

3

102

Total

629

352

981

1188

1188

30

30

2199

Events

42

30

72

74

74

0

0

146

Total

626

336

962

1256

1256

29

29

2247

Weight

29.0%

21.1%

50.1%

49.5%

49.5%

0.3%

0.3%

100.0%

M-H, Fixed, 95% CI

0.85 [0.55, 1.31]

0.70 [0.41, 1.19]

0.79 [0.56, 1.10]

0.59 [0.40, 0.85]

0.59 [0.40, 0.85]

6.77 [0.37, 125.65]

6.77 [0.37, 125.65]

0.71 [0.55, 0.91]


M-H, Fixed, 95% CI

0.005 0.1 1 10 200


Study or Subgroup


Crowther 2003

Marret 2006

Subtotal (95% CI)

Total events




Rouse 2008

Subtotal (95% CI)

Total events




Mittendorf 2002

Subtotal (95% CI)

Total events



Total (95% CI)

Total events



Events

123

56

179

144

144

5

5

328

Total

629

352

981

1188

1188

30

30

2199

Events

149

67

216

170

170

1

1

387

Total

626

336

962

1256

1256

29

29

2247

Weight

39.9%

18.2%

58.1%

41.4%

41.4%

0.5%

0.5%

100.0%

M-H, Random, 95% CI

0.82 [0.66, 1.02]

0.80 [0.58, 1.10]

0.81 [0.68, 0.97]

0.90 [0.73, 1.10]

0.90 [0.73, 1.10]

4.83 [0.60, 38.90]

4.83 [0.60, 38.90]

0.85 [0.74, 0.98]


M-H, Random, 95% CI

0.01 0.1 1 10 100



F 5: TIMING



Study or Subgroup


Crowther 2003

Marret 2006

Subtotal (95% CI)

Total events




Rouse 2008

Subtotal (95% CI)

Total events




Subtotal (95% CI)

Total events



Total (95% CI)

Total events



Events

18

18

36

20

20

0

56

Total

629

352

981

1188

1188

0

2169

Events

34

22

56

38

38

0

94

Total

626

336

962

1256

1256

0

2218

Weight

36.4%

24.1%

60.5%

39.5%

39.5%

100.0%

M-H, Fixed, 95% CI

0.53 [0.30, 0.92]

0.78 [0.43, 1.43]

0.63 [0.42, 0.95]

0.56 [0.33, 0.95]

0.56 [0.33, 0.95]

Not estimable

0.60 [0.43, 0.83]


M-H, Fixed, 95% CI

0.2 0.5 1 2 5


Study or Subgroup


Crowther 2003

Marret 2006

Subtotal (95% CI)

Total events




Rouse 2008

Subtotal (95% CI)

Total events




Subtotal (95% CI)

Total events



Total (95% CI)

Total events



Events

105

52

157

123

123

0

280

Total

629

352

981

1188

1188

0

2169

Events

141

60

201

134

134

0

335

Total

626

336

962

1256

1256

0

2218

Weight

39.8%

21.4%

61.2%

38.8%

38.8%

100.0%

M-H, Random, 95% CI

0.74 [0.59, 0.93]

0.83 [0.59, 1.16]

0.77 [0.63, 0.93]

0.97 [0.77, 1.22]

0.97 [0.77, 1.22]

Not estimable

0.84 [0.71, 1.00]


M-H, Random, 95% CI

0.5 0.7 1 1.5 2



F 5: TIMING



Study or Subgroup


Crowther 2003

Subtotal (95% CI)

Total events




Subtotal (95% CI)

Total events




Subtotal (95% CI)

Total events



Events

193

193

0

0

Total

629

629

0

0

Events

187

187

0

0

Total

626

626

0

0

Weight

100.0%

100.0%

M-H, Fixed, 95% CI

1.03 [0.87, 1.21]

1.03 [0.87, 1.21]

Not estimable

Not estimable


M-H, Fixed, 95% CI

0.5 0.7 1 1.5 2


Study or Subgroup


Crowther 2003

Marret 2006

Subtotal (95% CI)

Total events




Rouse 2008

Subtotal (95% CI)

Total events




Subtotal (95% CI)

Total events



Total (95% CI)

Total events



Events

176

57

233

406

406

0

639

Total

629

352

981

1188

1188

0

2169

Events

170

63

233

427

427

0

660

Total

626

336

962

1256

1256

0

2218

Weight

26.2%

9.9%

36.1%

63.9%

63.9%

100.0%

M-H, Fixed, 95% CI

1.03 [0.86, 1.23]

0.86 [0.62, 1.20]

0.98 [0.84, 1.15]

1.01 [0.90, 1.12]

1.01 [0.90, 1.12]

Not estimable

1.00 [0.91, 1.09]


M-H, Fixed, 95% CI

0.5 0.7 1 1.5 2



F 5: TIMING



Study or Subgroup


Crowther 2003

Subtotal (95% CI)

Total events




Subtotal (95% CI)

Total events




Subtotal (95% CI)

Total events



Events

89

89

0

0

Total

629

629

0

0

Events

78

78

0

0

Total

626

626

0

0

Weight

100.0%

100.0%

M-H, Fixed, 95% CI

1.14 [0.86, 1.51]

1.14 [0.86, 1.51]

Not estimable

Not estimable


M-H, Fixed, 95% CI

0.5 0.7 1 1.5 2


Study or Subgroup


Crowther 2003

Marret 2006

Subtotal (95% CI)

Total events




Rouse 2008

Subtotal (95% CI)

Total events




Mittendorf 2002

Subtotal (95% CI)

Total events



Total (95% CI)

Total events



Events

165

71

236

218

218

13

13

467

Total

629

352

981

1188

1188

85

85

2254

Events

148

82

230

252

252

11

11

493

Total

626

336

962

1256

1256

80

80

2298

Weight

34.5%

19.2%

53.7%

43.1%

43.1%

3.2%

3.2%

100.0%

M-H, Random, 95% CI

1.11 [0.92, 1.34]

0.83 [0.62, 1.09]

0.98 [0.73, 1.30]

0.91 [0.78, 1.08]

0.91 [0.78, 1.08]

1.11 [0.53, 2.34]

1.11 [0.53, 2.34]

0.96 [0.84, 1.10]


M-H, Random, 95% CI

0.2 0.5 1 2 5



F 5: TIMING



Study or Subgroup


Crowther 2003

Subtotal (95% CI)

Total events




Rouse 2008

Subtotal (95% CI)

Total events




Subtotal (95% CI)

Total events



Total (95% CI)

Total events



Events

49

49

23

23

0

72

Total

629

629

1188

1188

0

1817

Events

50

50

38

38

0

88

Total

626

626

1256

1256

0

1882

Weight

57.6%

57.6%

42.4%

42.4%

100.0%

M-H, Fixed, 95% CI

0.98 [0.67, 1.42]

0.98 [0.67, 1.42]

0.64 [0.38, 1.07]

0.64 [0.38, 1.07]

Not estimable

0.83 [0.62, 1.13]


M-H, Fixed, 95% CI

0.2 0.5 1 2 5


Study or Subgroup


Crowther 2003

Marret 2006

Subtotal (95% CI)

Total events




Rouse 2008

Subtotal (95% CI)

Total events




Mittendorf 2002

Subtotal (95% CI)

Total events



Total (95% CI)

Total events



Events

22

27

49

21

21

1

1

71

Total

629

352

981

1188

1188

85

85

2254

Events

21

28

49

27

27

0

0

76

Total

626

336

962

1256

1256

80

80

2298

Weight

27.5%

37.5%

65.0%

34.3%

34.3%

0.7%

0.7%

100.0%

M-H, Fixed, 95% CI

1.04 [0.58, 1.88]

0.92 [0.55, 1.53]

0.97 [0.66, 1.43]

0.82 [0.47, 1.45]

0.82 [0.47, 1.45]

2.83 [0.12, 68.37]

2.83 [0.12, 68.37]

0.93 [0.68, 1.28]


M-H, Fixed, 95% CI

0.01 0.1 1 10 100



F 5: TIMING

BLINDNESS

DEAFNESS

Study or Subgroup


Crowther 2003

Marret 2006

Subtotal (95% CI)

Total events




Subtotal (95% CI)

Total events




Subtotal (95% CI)

Total events



Total (95% CI)

Total events



Events

1

1

2

0

0

2

Total

629

352

981

0

0

981

Events

1

1

2

0

0

2

Total

626

336

962

0

0

962

Weight

49.5%

50.5%

100.0%

100.0%

M-H, Fixed, 95% CI

1.00 [0.06, 15.88]

0.95 [0.06, 15.20]

0.97 [0.14, 6.90]

Not estimable

Not estimable

0.97 [0.14, 6.90]


M-H, Fixed, 95% CI

0.01 0.1 1 10 100


Study or Subgroup


Crowther 2003

Marret 2006

Subtotal (95% CI)

Total events




Subtotal (95% CI)

Total events




Subtotal (95% CI)

Total events



Total (95% CI)

Total events



Events

8

0

8

0

0

8

Total

629

352

981

0

0

981

Events

7

4

11

0

0

11

Total

626

336

962

0

0

962

Weight

66.2%

33.8%

100.0%

100.0%

M-H, Random, 95% CI

1.14 [0.41, 3.12]

0.11 [0.01, 1.96]

0.51 [0.05, 4.96]

Not estimable

Not estimable

0.51 [0.05, 4.96]


M-H, Random, 95% CI

0.005 0.1 1 10 200



Q6: Regimens


Key question(s):

Q6: Do improvements to the fetus/infant/child vary by regimens?

1. Evidence base

Subgroup analysis from 4 RCTs; therefore the comparisons by regimens are non-randomised comparisons (level III).

B (Several Level lll studies with low

risk of bias) 2. Consistency

Unable to explain inconsistent results between Marret (2006) and Mittendorf (2002) for combined death and cerebral palsy; and cerebral palsy.

C (Some

inconsistency, reflecting genuine

uncertainty around question)

3. Clinical Impact

A (overall)

4. Generalisability

As for overall. B (Evidence directly generalisable to


5. Applicability

Australian and NZ clinicians may not be as comfortable with a 6 g loading dose and 2 g/hr maintenance dose.

A (Evidence directly


healthcare context)

Other factors


a) To make no recommendation regarding magnesium regimens b) To recommend that magnesium be given from 4 g to 6 g as loading dose and from 1 g to 2 g/hour

as a maintenance dose; with repeat doses possible with IV route c) To make a cautious recommendation that magnesium sulphate be only given as a 4 g loading dose

(over 20 minutes) and 1 g/hour maintenance dose with no repeat doses with IV route (up until birth or 24 hours whichever comes first).


Component Rating

Evidence base B

Consistency C


Generalisability B

Applicability A


RECOMMENDATION

Magnesium sulphate be given intravenously with a 4 gram loading dose (slowly over 20-30 minutes) and 1 gram per hour maintenance dose via intravenous route, with no immediate repeat doses. Continue regimen up until birth or 24 hours whichever comes first.

C

UNRESOLVED ISSUES




YES


YES


YES


Appendix F 6: Evidence Table and Graphs: REGIMENS

Study Loading

dose

Maintenance

dose

Repeat dosing Route

Marret 2006 4 g none none IV

Mittendorf 2002 4 g none none IV

Crowther 2003 4 g 1 g/hr none IV

Rouse 2008 6 g 2 g/hr 42.2% received repeat dose IV

IV= Intravenous

DEATH

Study or Subgroup

13.1.1 Loading dose 4 g (no maintenance)

Marret 2006

Mittendorf 2002

Subtotal (95% CI)

Total events



13.1.2 Loading 4 g (then 1 g/hr maintenance)

Crowther 2003

Subtotal (95% CI)

Total events



13.1.3 Loading dose 6 g (then 2 g/hr maintenance)

Rouse 2008

Subtotal (95% CI)

Total events



Total (95% CI)

Total events



Events

34

2

36

87

87

103

103

226

Total

352

30

382

629

629

1188

1188

2199

Events

38

1

39

107

107

96

96

242

Total

336

29

365

626

626

1256

1256

2247

Weight

16.2%

0.4%

16.6%

44.6%

44.6%

38.8%

38.8%

100.0%

M-H, Fixed, 95% CI

0.85 [0.55, 1.32]

1.93 [0.19, 20.18]

0.88 [0.57, 1.35]

0.81 [0.62, 1.05]

0.81 [0.62, 1.05]

1.13 [0.87, 1.48]

1.13 [0.87, 1.48]

0.95 [0.80, 1.12]


M-H, Fixed, 95% CI

0.05 0.2 1 5 20



F 6: REGIMENS

CEREBRAL PALSY


Study or Subgroup


Marret 2006

Mittendorf 2002

Subtotal (95% CI)

Total events




Crowther 2003

Subtotal (95% CI)

Total events




Rouse 2008

Subtotal (95% CI)

Total events



Total (95% CI)

Total events



Events

22

3

25

36

36

41

41

102

Total

352

30

382

629

629

1188

1188

2199

Events

30

0

30

42

42

74

74

146

Total

336

29

365

626

626

1256

1256

2247

Weight

25.1%

1.1%

26.2%

33.6%

33.6%

40.2%

40.2%

100.0%

M-H, Random, 95% CI

0.70 [0.41, 1.19]

6.77 [0.37, 125.65]

1.37 [0.18, 10.70]

0.85 [0.55, 1.31]

0.85 [0.55, 1.31]

0.59 [0.40, 0.85]

0.59 [0.40, 0.85]

0.71 [0.52, 0.97]


M-H, Random, 95% CI

0.005 0.1 1 10 200


Study or Subgroup


Marret 2006

Mittendorf 2002

Subtotal (95% CI)

Total events




Crowther 2003

Subtotal (95% CI)

Total events




Rouse 2008

Subtotal (95% CI)

Total events



Total (95% CI)

Total events



Events

56

5

61

123

123

144

144

328

Total

352

30

382

629

629

1188

1188

2199

Events

67

1

68

149

149

170

170

387

Total

336

29

365

626

626

1256

1256

2247

Weight

18.2%

0.5%

18.7%

39.9%

39.9%

41.4%

41.4%

100.0%

M-H, Random, 95% CI

0.80 [0.58, 1.10]

4.83 [0.60, 38.90]

1.45 [0.27, 7.72]

0.82 [0.66, 1.02]

0.82 [0.66, 1.02]

0.90 [0.73, 1.10]

0.90 [0.73, 1.10]

0.85 [0.74, 0.98]


M-H, Random, 95% CI

0.02 0.1 1 10 50



F 6: REGIMENS



Study or Subgroup


Marret 2006

Subtotal (95% CI)

Total events




Crowther 2003

Subtotal (95% CI)

Total events




Rouse 2008

Subtotal (95% CI)

Total events



Total (95% CI)

Total events



Events

18

18

18

18

20

20

56

Total

352

352

629

629

1188

1188

2169

Events

22

22

34

34

38

38

94

Total

336

336

626

626

1256

1256

2218

Weight

24.1%

24.1%

36.4%

36.4%

39.5%

39.5%

100.0%

M-H, Fixed, 95% CI

0.78 [0.43, 1.43]

0.78 [0.43, 1.43]

0.53 [0.30, 0.92]

0.53 [0.30, 0.92]

0.56 [0.33, 0.95]

0.56 [0.33, 0.95]

0.60 [0.43, 0.83]


M-H, Fixed, 95% CI

0.2 0.5 1 2 5


Study or Subgroup


Marret 2006

Subtotal (95% CI)

Total events




Crowther 2003

Subtotal (95% CI)

Total events




Rouse 2008

Subtotal (95% CI)

Total events



Total (95% CI)

Total events



Events

52

52

105

105

123

123

280

Total

352

352

629

629

1188

1188

2169

Events

60

60

141

141

134

134

335

Total

336

336

626

626

1256

1256

2218

Weight

21.4%

21.4%

39.8%

39.8%

38.8%

38.8%

100.0%

M-H, Random, 95% CI

0.83 [0.59, 1.16]

0.83 [0.59, 1.16]

0.74 [0.59, 0.93]

0.74 [0.59, 0.93]

0.97 [0.77, 1.22]

0.97 [0.77, 1.22]

0.84 [0.71, 1.00]


M-H, Random, 95% CI

0.5 0.7 1 1.5 2



F 6: REGIMENS



Study or Subgroup

13.3.1 Loading dose 4g (no maintenance)

Subtotal (95% CI)

Total events



13.3.2 Loading dose 4 g (then 1g/hr maintenance)

Crowther 2003

Subtotal (95% CI)

Total events



13.3.3 Loading dose 6g (then 2g/hr maintenance)

Subtotal (95% CI)

Total events



Total (95% CI)

Total events



Events

0

193

193

0

193

Total

0

629

629

0

629

Events

0

187

187

0

187

Total

0

626

626

0

626

Weight

100.0%

100.0%

100.0%

M-H, Fixed, 95% CI

Not estimable

1.03 [0.87, 1.21]

1.03 [0.87, 1.21]

Not estimable

1.03 [0.87, 1.21]


M-H, Fixed, 95% CI

0.5 0.7 1 1.5 2


Study or Subgroup


Marret 2006

Subtotal (95% CI)

Total events




Crowther 2003

Subtotal (95% CI)

Total events




Rouse 2008

Subtotal (95% CI)

Total events



Total (95% CI)

Total events



Events

57

57

176

176

406

406

639

Total

352

352

629

629

1188

1188

2169

Events

63

63

170

170

427

427

660

Total

336

336

626

626

1256

1256

2218

Weight

9.9%

9.9%

26.2%

26.2%

63.9%

63.9%

100.0%

M-H, Fixed, 95% CI

0.86 [0.62, 1.20]

0.86 [0.62, 1.20]

1.03 [0.86, 1.23]

1.03 [0.86, 1.23]

1.01 [0.90, 1.12]

1.01 [0.90, 1.12]

1.00 [0.91, 1.09]


M-H, Fixed, 95% CI

0.5 0.7 1 1.5 2



F 6: REGIMENS



Study or Subgroup

13.4.2 Loading dose 4g (no maintenance)

Subtotal (95% CI)

Total events



13.4.3 Loading dose 4 g (then 1g/hr maintenance)

Crowther 2003

Subtotal (95% CI)

Total events



13.4.4 Loading dose 6g (then 2g/hr maintenance)

Subtotal (95% CI)

Total events



Total (95% CI)

Total events



Events

0

89

89

0

89

Total

0

629

629

0

629

Events

0

78

78

0

78

Total

0

626

626

0

626

Weight

100.0%

100.0%

100.0%

M-H, Fixed, 95% CI

Not estimable

1.14 [0.86, 1.51]

1.14 [0.86, 1.51]

Not estimable

1.14 [0.86, 1.51]


M-H, Fixed, 95% CI

0.5 0.7 1 1.5 2


Study or Subgroup


Marret 2006

Mittendorf 2002

Subtotal (95% CI)

Total events




Crowther 2003

Subtotal (95% CI)

Total events




Rouse 2008

Subtotal (95% CI)

Total events



Total (95% CI)

Total events



Events

71

13

84

165

165

218

218

467

Total

352

85

437

629

629

1188

1188

2254

Events

82

11

93

148

148

252

252

493

Total

336

80

416

626

626

1256

1256

2298

Weight

17.2%

2.3%

19.5%

30.4%

30.4%

50.1%

50.1%

100.0%

M-H, Fixed, 95% CI

0.83 [0.62, 1.09]

1.11 [0.53, 2.34]

0.86 [0.66, 1.12]

1.11 [0.92, 1.34]

1.11 [0.92, 1.34]

0.91 [0.78, 1.08]

0.91 [0.78, 1.08]

0.96 [0.86, 1.08]


M-H, Fixed, 95% CI

0.2 0.5 1 2 5



F 6: REGIMENS



Study or Subgroup


Subtotal (95% CI)

Total events




Crowther 2003

Subtotal (95% CI)

Total events




Rouse 2008

Subtotal (95% CI)

Total events



Total (95% CI)

Total events



Events

0

49

49

23

23

72

Total

0

629

629

1188

1188

1817

Events

0

50

50

38

38

88

Total

0

626

626

1256

1256

1882

Weight

57.6%

57.6%

42.4%

42.4%

100.0%

M-H, Fixed, 95% CI

Not estimable

0.98 [0.67, 1.42]

0.98 [0.67, 1.42]

0.64 [0.38, 1.07]

0.64 [0.38, 1.07]

0.83 [0.62, 1.13]


M-H, Fixed, 95% CI

0.2 0.5 1 2 5


Study or Subgroup


Marret 2006

Mittendorf 2002

Subtotal (95% CI)

Total events




Crowther 2003

Subtotal (95% CI)

Total events




Rouse 2008

Subtotal (95% CI)

Total events



Total (95% CI)

Total events



Events

27

1

28

22

22

21

21

71

Total

352

85

437

629

629

1188

1188

2254

Events

28

0

28

21

21

27

27

76

Total

336

80

416

626

626

1256

1256

2298

Weight

37.5%

0.7%

38.1%

27.5%

27.5%

34.3%

34.3%

100.0%

M-H, Fixed, 95% CI

0.92 [0.55, 1.53]

2.83 [0.12, 68.37]

0.95 [0.58, 1.57]

1.04 [0.58, 1.88]

1.04 [0.58, 1.88]

0.82 [0.47, 1.45]

0.82 [0.47, 1.45]

0.93 [0.68, 1.28]


M-H, Fixed, 95% CI

0.01 0.1 1 10 100



F 6: REGIMENS

BLINDNESS

DEAFNESS

Study or Subgroup


Marret 2006

Subtotal (95% CI)

Total events




Crowther 2003

Subtotal (95% CI)

Total events




Subtotal (95% CI)

Total events



Total (95% CI)

Total events



Events

1

1

1

1

0

2

Total

352

352

629

629

0

981

Events

1

1

1

1

0

2

Total

336

336

626

626

0

962

Weight

50.5%

50.5%

49.5%

49.5%

100.0%

M-H, Fixed, 95% CI

0.95 [0.06, 15.20]

0.95 [0.06, 15.20]

1.00 [0.06, 15.88]

1.00 [0.06, 15.88]

Not estimable

0.97 [0.14, 6.90]


M-H, Fixed, 95% CI

0.02 0.1 1 10 50


Study or Subgroup


Marret 2006

Subtotal (95% CI)

Total events




Crowther 2003

Subtotal (95% CI)

Total events




Subtotal (95% CI)

Total events



Total (95% CI)

Total events



Events

0

0

8

8

0

8

Total

352

352

629

629

0

981

Events

4

4

7

7

0

11

Total

336

336

626

626

0

962

Weight

33.8%

33.8%

66.2%

66.2%

100.0%

M-H, Random, 95% CI

0.11 [0.01, 1.96]

0.11 [0.01, 1.96]

1.14 [0.41, 3.12]

1.14 [0.41, 3.12]

Not estimable

0.51 [0.05, 4.96]


M-H, Random, 95% CI

0.005 0.1 1 10 200



Q7: Number of babies in utero


Key question(s):

Q7: Do improvements to the fetus/infant/child vary by number of babies in utero?

1. Evidence base

Subgroup analysis from 4 RCTs; therefore the comparisons by the number of babies in utero are non-randomised comparisons (level III).





3. Clinical Impact

Very large A (overall)

4. Generalisability



5. Applicability

No evidence to suggest that benefit is specific to either single or multiple (up to 4) babies in utero

A (Evidence directly


healthcare context) Other factors


a) To make no recommendation regarding magnesium regimens; b) To make a cautious recommendation that magnesium sulphate be given to women with up to 4

babies in utero; c) To make a recommendation that magnesium sulphate be given to women regardless of plurality.


Component Rating

Evidence base B

Consistency B


Generalisability B

Applicability A


RECOMMENDATION

Magnesium sulphate be given to women regardless of plurality. B

UNRESOLVED ISSUES





YES


YES


YES


F 7: Evidence Tables and Graphs: NUMBER OF BABIES IN UTERO

Study Single Twin Higher order Reported separately

Crowther 2003 Yes Yes Yes (triplet+quad) Single vs multiple

Rouse 2008 Yes Yes No Single vs twin

Marret 2006 Yes Yes Yes (triplet) No

Mittendorf 2002 Yes Yes No No

DEATH

Study or Subgroup

14.1.1 Single

Crowther 2003

Rouse 2008

Subtotal (95% CI)

Total events



14.1.2 Multiple

Crowther 2003

Rouse 2008

Subtotal (95% CI)

Total events



14.1.3 Mixed

Marret 2006

Mittendorf 2002

Subtotal (95% CI)

Total events



Total (95% CI)

Total events



Events

60

83

143

27

16

43

34

2

36

222

Total

447

950

1397

182

91

273

352

30

382

2052

Events

73

75

148

34

18

52

38

1

39

239

Total

438

985

1423

188

110

298

336

29

365

2086

Weight

29.6%

32.9%

62.5%

13.8%

7.8%

21.6%

15.4%

0.5%

15.9%

100.0%

M-H, Random, 95% CI

0.81 [0.59, 1.10]

1.15 [0.85, 1.55]

0.96 [0.68, 1.37]

0.82 [0.52, 1.30]

1.07 [0.58, 1.98]

0.90 [0.63, 1.31]

0.85 [0.55, 1.32]

1.93 [0.19, 20.18]

0.88 [0.57, 1.35]

0.94 [0.79, 1.12]


M-H, Random, 95% CI

0.05 0.2 1 5 20



F 7: NUMBER OF BABIES IN UTERO

CEREBRAL PALSY


Study or Subgroup

14.2.1 Single

Crowther 2003

Subtotal (95% CI)

Total events



14.2.2 Multiple

Crowther 2003

Subtotal (95% CI)

Total events



14.2.3 Mixed

Marret 2006

Mittendorf 2002

Rouse 2008

Subtotal (95% CI)

Total events



Total (95% CI)

Total events



Events

29

29

7

7

22

3

41

66

102

Total

447

447

182

182

352

30

1188

1570

2199

Events

28

28

14

14

30

0

74

104

146

Total

438

438

188

188

336

29

1256

1621

2247

Weight

19.5%

19.5%

9.5%

9.5%

21.1%

0.3%

49.5%

71.0%

100.0%

M-H, Fixed, 95% CI

1.01 [0.61, 1.68]

1.01 [0.61, 1.68]

0.52 [0.21, 1.25]

0.52 [0.21, 1.25]

0.70 [0.41, 1.19]

6.77 [0.37, 125.65]

0.59 [0.40, 0.85]

0.65 [0.48, 0.88]

0.71 [0.55, 0.91]


M-H, Fixed, 95% CI

0.005 0.1 1 10 200


Study or Subgroup

14.5.1 Single

Crowther 2003

Subtotal (95% CI)

Total events



14.5.2 Multiple

Crowther 2003

Subtotal (95% CI)

Total events



14.5.3 Mixed

Marret 2006

Mittendorf 2002

Rouse 2008

Subtotal (95% CI)

Total events



Total (95% CI)

Total events



Events

89

89

34

34

56

5

144

205

328

Total

447

447

182

182

352

30

1188

1570

2199

Events

101

101

48

48

67

1

170

238

387

Total

438

438

188

188

336

29

1256

1621

2247

Weight

28.3%

28.3%

11.9%

11.9%

17.4%

0.4%

42.0%

59.8%

100.0%

M-H, Random, 95% CI

0.86 [0.67, 1.11]

0.86 [0.67, 1.11]

0.73 [0.50, 1.08]

0.73 [0.50, 1.08]

0.80 [0.58, 1.10]

4.83 [0.60, 38.90]

0.90 [0.73, 1.10]

0.88 [0.68, 1.14]

0.85 [0.75, 0.98]


M-H, Random, 95% CI

0.02 0.1 1 10 50



F 7: NUMBER OF BABIES IN UTERO



Study or Subgroup

14.3.1 Single

Crowther 2003

Subtotal (95% CI)

Total events



14.3.2 Multiple

Crowther 2003

Subtotal (95% CI)

Total events



14.3.3 Mixed

Subtotal (95% CI)

Total events



Total (95% CI)

Total events



Events

149

149

44

44

0

193

Total

447

447

182

182

0

629

Events

136

136

51

51

0

187

Total

438

438

188

188

0

626

Weight

73.2%

73.2%

26.8%

26.8%

100.0%

M-H, Fixed, 95% CI

1.07 [0.89, 1.30]

1.07 [0.89, 1.30]

0.89 [0.63, 1.26]

0.89 [0.63, 1.26]

Not estimable

1.02 [0.87, 1.21]


M-H, Fixed, 95% CI

0.5 0.7 1 1.5 2


Study or Subgroup

14.4.1 Single

Crowther 2003

Subtotal (95% CI)

Total events



14.4.2 Multiple

Crowther 2003

Subtotal (95% CI)

Total events



14.4.3 Mixed

Subtotal (95% CI)

Total events



Total (95% CI)

Total events



Events

71

71

18

18

0

89

Total

447

447

182

182

0

629

Events

56

56

22

22

0

78

Total

438

438

188

188

0

626

Weight

72.3%

72.3%

27.7%

27.7%

100.0%

M-H, Fixed, 95% CI

1.24 [0.90, 1.72]

1.24 [0.90, 1.72]

0.85 [0.47, 1.52]

0.85 [0.47, 1.52]

Not estimable

1.13 [0.85, 1.50]


M-H, Fixed, 95% CI

0.5 0.7 1 1.5 2



Q8: Reason for treatment


Key question(s):

Q8: Do improvements to the fetus/infant/child vary by reason women considered (at less than 30 weeks gestation) to be at risk of preterm birth?

1. Evidence base

Subgroup analysis from 4 RCTs; therefore the comparisons by time magnesium is planned are non-randomised comparisons (level III).





3. Clinical Impact


4. Generalisability



5. Applicability

As for overall. A (Evidence directly


healthcare context)

Other factors


a) To make no recommendation regarding reason for treatment with magnesium sulphate; b) To recommend that magnesium be given to all women regardless of whether reason for treatment

is PROM, preterm labour or preterm birth; c) To make a cautious recommendation that magnesium sulphate be only given to women at risk of

preterm birth within 24 hours.


Component Rating

Evidence base B

Consistency B


Generalisability B

Applicability A


RECOMMENDATION

Magnesium sulphate be given regardless of reason women considered (at less than 30 weeks’ gestation) to be at risk of preterm birth.

B

UNRESOLVED ISSUES

Individual patient data meta-analysis needed




YES


YES


YES


Q9: Parity Of Women


Key question(s):

Q9: Do improvements to the fetus/infant/child vary by parity of women?

1. Evidence base

Subgroup analysis from 4 RCTs; therefore the comparisons by parity of women are non-randomised comparisons (level III).





3. Clinical Impact


4. Generalisability



5. Applicability



healthcare context)

Other factors


a) To make no recommendation regarding giving magnesium sulphate to women based on parity; b) To recommend that magnesium sulphate be given to all women regardless of parity.


Component Rating

Evidence base B

Consistency B


Generalisability B

Applicability A


RECOMMENDATION

Magnesium sulphate be given to all women regardless of parity (number of previous births for the woman).

B

UNRESOLVED ISSUES





YES


YES


YES


Q10: Mode Of Birth


Key question(s):

Q10: Do improvements to the fetus/infant/child vary by mode of birth?

1. Evidence base






3. Clinical Impact


4. Generalisability



5. Applicability

As for overall. A

(Evidence directly applicable to

Australian healthcare context)

Other factors


a) To make no recommendation regarding giving magnesium sulphate to women based on mode of birth;

b) To recommend that magnesium sulphate be given to all women regardless of mode of birth.


Component Rating

Evidence base B

Consistency B


Generalisability B

Applicability A


RECOMMENDATION

Magnesium sulphate be given to all women regardless of mode of birth. B

UNRESOLVED ISSUES





YES


YES


YES


Appendix F 10: Evidence Table and Graphs: MODE OF BIRTH

Study Caesarean Section Vaginal Birth

Crowther 2003 Yes Yes

Rouse 2008 Yes Yes

Marret 2006 Yes Yes

Mittendorf 2002 No No

CAESAREAN SECTION

VAGINAL BIRTH

Study or Subgroup

Crowther 2003

Marret 2006

Rouse 2008

Total (95% CI)

Total events



Events

289

116

417

822

Total

535

286

1096

1917

Events

290

96

448

834

Total

527

278

1145

1950

Weight

35.3%

11.8%

52.9%

100.0%

M-H, Fixed, 95% CI

0.98 [0.88, 1.10]

1.17 [0.95, 1.46]

0.97 [0.88, 1.08]

1.00 [0.93, 1.07]


M-H, Fixed, 95% CI

0.5 0.7 1 1.5 2


Study or Subgroup

Crowther 2003

Marret 2006

Rouse 2008

Total (95% CI)

Total events



Events

246

170

679

1095

Total

535

286

1096

1917

Events

237

182

697

1116

Total

527

278

1145

1950

Weight

21.6%

16.7%

61.7%

100.0%

M-H, Fixed, 95% CI

1.02 [0.90, 1.17]

0.91 [0.80, 1.03]

1.02 [0.95, 1.09]

1.00 [0.95, 1.06]


M-H, Fixed, 95% CI

0.5 0.7 1 1.5 2



Q11: Combined Effect Of Antenatal Corticosteroids


Key question(s):

Q11: Do improvements to the fetus/infant/child vary by combined effect of antenatal corticosteroids and magnesium sulphate?

1. Evidence base


B (Several Level lll studies

with low risk of bias) 2. Consistency

B (Most studies consistent and inconsistency can be

explained) 3. Clinical Impact


4. Generalisability

As for overall. B (Evidence directly


caveats)

5. Applicability


applicable to Australian healthcare context)

Other factors


a) To make no recommendation regarding giving magnesium sulphate to women receiving antenatal corticosteroids;

b) To recommend that magnesium sulphate be given to all women whether or not antenatal corticosteroids have been given.


Component Rating

Evidence base B

Consistency B


Generalisability B

Applicability A


RECOMMENDATION

Magnesium sulphate be given to all women whether or not antenatal corticosteroids have been given.

B

UNRESOLVED ISSUES





YES


YES


YES


Appendix F 11: Evidence Table and Graphs: COMBINED EFFECT OF ANTENATAL CORTICOSTEROIDS

Study High use of antenatal corticosteroids

Crowther 2003 yes

Rouse 2008 yes

Marret 2006 yes

Mittendorf 2002 unknown

DEATH

CEREBRAL PALSY

Study or Subgroup

16.4.1 High

Crowther 2003

Marret 2006

Rouse 2008

Subtotal (95% CI)

Total events



16.4.2 Unknown

Mittendorf 2002

Subtotal (95% CI)

Total events



Total (95% CI)

Total events



Events

87

34

103

224

2

2

226

Total

629

352

1188

2169

30

30

2199

Events

107

38

96

241

1

1

242

Total

626

336

1256

2218

29

29

2247

Weight

44.6%

16.2%

38.8%

99.6%

0.4%

0.4%

100.0%

M-H, Fixed, 95% CI

0.81 [0.62, 1.05]

0.85 [0.55, 1.32]

1.13 [0.87, 1.48]

0.94 [0.79, 1.12]

1.93 [0.19, 20.18]

1.93 [0.19, 20.18]

0.95 [0.80, 1.12]


M-H, Fixed, 95% CI

0.02 0.1 1 10 50


Study or Subgroup

16.5.1 High

Crowther 2003

Marret 2006

Rouse 2008

Subtotal (95% CI)

Total events



16.5.2 Unknown

Mittendorf 2002

Subtotal (95% CI)

Total events



Total (95% CI)

Total events



Events

36

22

41

99

3

3

102

Total

629

352

1188

2169

30

30

2199

Events

42

30

74

146

0

0

146

Total

626

336

1256

2218

29

29

2247

Weight

29.0%

21.1%

49.5%

99.7%

0.3%

0.3%

100.0%

M-H, Fixed, 95% CI

0.85 [0.55, 1.31]

0.70 [0.41, 1.19]

0.59 [0.40, 0.85]

0.69 [0.54, 0.88]

6.77 [0.37, 125.65]

6.77 [0.37, 125.65]

0.71 [0.55, 0.91]


M-H, Fixed, 95% CI

0.005 0.1 1 10 200



F 11: COMBINED EFFECT OF ANTENATAL CORTICOSTEROIDS


Study or Subgroup

16.6.1 High

Crowther 2003

Marret 2006

Rouse 2008

Subtotal (95% CI)

Total events



16.6.2 Unknown

Mittendorf 2002

Subtotal (95% CI)

Total events



Total (95% CI)

Total events



Events

123

56

144

323

5

5

328

Total

629

352

1188

2169

30

30

2199

Events

149

67

170

386

1

1

387

Total

626

336

1256

2218

29

29

2247

Weight

39.9%

18.2%

41.4%

99.5%

0.5%

0.5%

100.0%

M-H, Random, 95% CI

0.82 [0.66, 1.02]

0.80 [0.58, 1.10]

0.90 [0.73, 1.10]

0.85 [0.74, 0.97]

4.83 [0.60, 38.90]

4.83 [0.60, 38.90]

0.85 [0.74, 0.98]


M-H, Random, 95% CI

0.02 0.1 1 10 50



Appendix G: Harms – Maternal; and Fetus, Infant, and Child

Maternal Harms

Effect (95% CI) No of trials

No of women

Trial references Source

CESSATION OF MATERNAL THERAPY

RR 3.12 (2.35 to 4.15) 2 3,293 Crowther 2003; Rouse 2008 Doyle 2009 (CR)

181/1631 (11.1%) vs 59/1672 (3.5%)

RR 1.59 (0.57 to 4.41) 4 310 Cotton 1984; Cox 1990; Fox 1993; Ma 1992;

Crowther 2002 (CR)

8/151 (5.3%) vs 7/159 (4.4%)

RR 2.69 (2.18 to 3.31) 1 10,110 Magpie 2002 Magpie 2002

317/4999 (6.3%) vs 118/4993 (2.4%)

Not reported in any trials Crowther 1998 (CR)

HYPOTENSION

RR 1.90 (1.11 to 3.26) 1 9,992 Magpie 2002 Duley 2003 (CR)

RR 1.51 (1.09 to 2.09) 2 1,626 Crowther 2003; Marret 2006 Doyle 2009 (CR)

RR 3.16 (0.13 to 76.30) 1 156 Cox 1990 Crowther 2002 (CR)

Overall RR 1.63 (1.23 to 2.15) 119/5896 (2.0%) vs 72/5828 (1.2%)

Not reported in any trials Crowther 1998 (CR)

RESPIRATORY DEPRESSION OR OTHER RESPIRATORY PROBLEM

RR 1.98 (1.24 to 3.15) 2 10,667 Magpie 2002; South Africa 1998 Duley 2003 (CR)

RR 1.31 (0.83 to 2.07) 2 3,303 Crowther 2003; Rouse 2008 Doyle 2009 (CR)

Overall RR 1.62 (1.17 to 2.24) 93/6975 (1.3%) vs 57/7005 (0.8%)

RESPIRATORY ARREST

RR 1.02 (0.06 to 16.25) 4 5,411 Crowther 2003; Magpie 2006; Marret 2006; Rouse 2008

Doyle 2009 (CR)



TENDON REFLEXES (absent or reduced)


TACHYCARDIA

RR 0.0 (0.0 to 0.0) 1 35 Cotton 1984 Crowther 2002 (CR)

RR 1.53 (1.03 to 2.29) 1 1,062 Crowther 2003 Doyle 2009 (CR)

RR 1.05 (0.15 to 7.21) 1 133 Rust 1996 Crowther 1998 (CR)

CARDIAC ARREST

RR 0.34 (0.04 to 3.26) 4 5,411 Crowther 2003; Magpie 2006; Marret 2006; Rouse 2008

Doyle 2009 (CR)


CAESAREAN

RR 1.05 (1.01 to 1.10) 6 10,108 Magpie 2002; South Africa 1994; South Africa 1998; Taiwan 1995; Memphis 1997; Tennessee 2001

Duley 2003 (CR)

2528/5082 (49.7%) vs 2370/5026 (47.2%)

RR 1.07 (0.62 to 1.83) 3 281 Cotton 1984; Cox 1990; Fox 1993 Crowther 2002 (CR)

RR 1.00 (0.93 to 1.07) 3 2,323 Crowther 2003; Marret 2006; Rouse 2008

Doyle 2009 (CR)

MORTALITY

RR 0.32 (0.01 to 7.92) 3 2,323 Crowther 2003; Marret 2006; Doyle 2009 (CR)


Rouse 2008


ADMISSION TO ICU

RR 0.89 (0.54 to 1.47) 2 2,606 Crowther 2003; Magpie 2006 (part) Doyle 2009 (CR)

HOSPITAL STAY (days)

MD 0.17 (-0.18 to 0.53) 2 2,606 Crowther 2003; Magpie 2006 (part) Doyle 2009 (CR)

POSTPARTUM HAEMORRHAGE

RR 0.87 (0.67 to 1.12) 2 1,626 Crowther 2003; Marret 2006 Doyle 2009 (CR)

RR 0.96 (0.88 to 1.05) 2 8,909 Magpie 2002; Memphis 1997 Duley 2003 (CR)

ANY SIDE EFFECTS



1201/4999 (24.0%) vs 228/4993 (4.6%)

FLUSHING

RR 9.38 (7.74 to 11.37) 2 10,127 Magpie 2002; Memphis 1997 Duley 2003 (CR)

NAUSEA/VOMITING


RR 0.73 (0.30 to 1.81) nausea only

1 133 Rust 1996 Crowther 1998 (CR)

RR 0.42 (0.08 to 2.08) vomiting only

1 133 Rust 1996 Crowther 1998 (CR)

DIARRHOEA

RR 7.67 (2.41 to 24.41) 1 133 Rust 1996 Crowther 1998 CR)

ABDOMINAL PAIN

RR 0.0 (0.0 to 0.0) 0 0 0 Crowther 1998 (CR)

CHEST PAIN

RR 0.0 (0.0 to 0.0) 0 0 0 Crowther 1998 (CR)

STROKE


GIVEN CALCIUM GLUCONATE


SLURRED SPEECH

RR 3.04 (0.13 to 73.42) 1 135 Memphis 1997 Duley 2003 (CR)

MUSCLE WEAKNESS


DIZZINESS


DROWSINESS/CONFUSION


HEADACHE


PROBLEM AT INJECTION SITE (INTRAMUSCULAR OR INTRAVENOUS)


INDUCTION OF LABOUR


BLOOD TRANSFUSION


RR = risk ratio: MD = mean difference


Fetus, Infant and Child

Effect (95% CI) No of trials

No of women /infants

Trial references Source

FETAL DEATHS


RR 0.78 (0.42 to 1.46) 4 4,446 Crowther 2003; Marret 2006 Mittendorf 2002 (neuroprotective); Rouse 2008

Doyle 2009 (CR)

RR 0.99 (0.87 to 1.12) 3 9,961 Magpie 2002; South Africa 1998 South Africa 1994

Duley 2003 (CR)

NEONATAL AND INFANT DEATHS


TOTAL DEATHS (FETAL, NEONATAL AND INFANT)


RR 0.95 (0.80 to 1.12) 4 4,446 Crowther 2003; Marret 2006; Mittendorf 2002; Rouse 2008

Doyle 2009 (CR)

RR 5.00 (0.25 to 99.16) 1 50 Ricci 1991 Crowther 1998 (CR)

ASSISTED VENTILATION


NECROTISING ENTEROCOLITIS (NEC)


ADMISSION TO NEONATAL ICU/SCN




APGAR SCORE <7 at 5 MINUTES

RR 1.03 (0.90 to 1.18) 3 4,387 Crowther 2003 Marret 2006 Rouse 2008

Doyle 2009 (CR)


NEONATAL CONVULSIONS

RR 0.80 (0.56 to 1.13) 3 4,387 Crowther 2003 Marret 2006 Rouse 2008

Doyle 2009 (CR)

NEONATAL HYPOTONIA

RR 1.02 (0.77 to 1.36) 1 2,444 Rouse 2008 Doyle 2009 (CR)

CHRONIC LUNG DISEASE (oxygen at 36 days)

RR 1.12 (0.95 to 1.32) 2 1,943 Crowther 2003 Marret 2006

Doyle 2009 (CR)

CHRONIC LUNG DISEASE (oxygen at 28 days)

RR 1.07 (0.94 to 1.22) 1 1,255 Crowther 2003 Doyle 2009 (CR)

INTRAVENTRICULAR HAEMORRHAGE TOTAL

RR 0.86 (0.28 to 2.62) 3 289 Cotton 1984 Cox 1990 Fox 1993

Crowther 2002 (CR)

RR 3.00 (0.13 to 70.30) 1 50 Ricci 1991 Crowther 1998 (CR)

RR 0.96 (0.86 to 1.08) 4 4,552 Crowther 2003 Marret 2006 Mittendorf 2002 Rouse 2008

Doyle 2009 (CR)

INTRAVENTRICULAR HAEMORRHAGE (SEVERE GRADES 3 & 4)


RR 0.0 1 90 Fox 1993 Crowther 2002 (CR)

RR 0.83 (0.62 to 1.13) 2 3699 Crowther 2003 Rouse 2008

Doyle 2009 (CR)

INTRAVENTRICULAR HAEMORRAGE (SEVERE GRADES 3 & 4) OR PVL




RR 0.93 (0.68 to 1.28) 4 4,552 Crowther 2003 Marret 2006 Mittendorf 2002 Rouse 2008

Doyle 2009 (CR)

NEONATAL LENGTH OF STAY

MD 1.18 (-0.46 to 2.82) days

2 180 Ricci 1991 Rust 1996

Crowther 1998 (CR)

RR 1.02 (0.93 to 1.11) (> 7 days)

1 8,260 Magpie 2002 Duley 2003 (CR)


Appendix H: Additional Information about Regimens and Monitoring for giving Magnesium Sulphate to Prevent

Eclampsia from Clinical Practice Guidelines and Management Protocols

Condition The Society of Obstetric Medicine of Australia and New Zealand (SOMANZ) recommend magnesium sulphate as the drug of choice for prophylaxis against eclampsia for women with preeclampsia. The World Health Organization (WHO), Royal College of Obstetricians and Gynaecologists (RCOG) and Society of Obstetricians and Gynaecologists of Canada (SOGC) give more cautious recommendations, indicating that treatment with magnesium sulphate is recommended in severe pre-eclampsia. SOGC qualifies this by indicating that magnesium sulphate may be given for women with non-severe preeclampsia. SOGC does not give any guidelines on recommended dosage regimens. RCOG indicates that in cases of less severe disease the decision is less clear and will depend on an individual case assessment. The New South Wales Department of Health is more conservative indicating it is appropriate for use for seizure prophylaxis in a woman who has already had an eclamptic seizure and indicates that the efficacy is less certain for use as a seizure prophylaxis in a woman with severe pre-eclampsia who is at risk of eclampsia (Table H1).

Loading Dose

A loading dose of 4 g of magnesium sulphate is recommended by all those guidelines that specified doses. Administration recommendations for the loading dose vary

when administered by infusion pumps, with both the volume and time of administration differing. However, the syringe pump administration recommendations are

similar. RCOG and SOMANZ do not give any recommendation for the administration of the loading dose in either the infusion or syringe pump. SOMANZ indicate

that it is appropriate that obstetric units determine their own protocols. The Royal Women’s Hospital (Victoria) guidelines do not give any recommendation for the

administration of the loading dose by infusion pump (Table H2).

Maintenance dose

Most of the guidelines consulted who specified doses recommend 1 g of magnesium sulphate per hour as a maintenance dose. SOMANZ is the exception with 1-2 g

of magnesium sulphate per hour recommended as a maintenance dose. All guidelines who specified doses recommend a maintenance period of 24 hrs either after

birth and/or 24 hrs after last seizure. RCOG and SOMANZ do not give any recommendation for the administration of the maintenance dose in either the infusion or

syringe pump. SOMANZ indicate that it is appropriate that obstetric units determine their own protocols. In addition, the South Australian guidelines recommend a

total daily dose not exceeding 30-40 g of magnesium sulphate (Table H3).

Monitoring

SOMANZ recommend monitoring of serum levels of magnesium sulphate, however they indicate that it is appropriate that obstetric units determine their own

protocols for monitoring outcomes. RCOG recommend ‘regular assessment’ but give no indication of timing. The Royal Women’s Hospital (Victoria) guidelines

recommend monitoring for 4 hrs following the discontinuation of the magnesium infusion (Tables H4 and H5).


Table H.1: Magnesium sulphate recommendation for condition

Guidelines Condition

NSW Seizure prophylaxis in a woman with severe pre-eclampsia who is at risk of eclampsia (although efficacy for this is less certain).

Seizure prophylaxis in a woman who has already had an eclamptic seizure.

The Royal Women’s Hosp, VIC Women with preeclampsia for whom there concern about the risk of eclampsia.

Management of an eclamptic seizure.

SA Pre-eclampsia to prevent eclampsia (prophylaxis).

For eclamptic seizures.

RCOG Consider for severe pre-eclampsia where there is concern about risk of eclampsia.

Women with less severe pre-eclampsia, the decision to use MgSO4 is less clear and depends on the individual case.

Eclampsia for seizures.

SOMANZ Preeclampsia (prevention of eclampsia).

For eclamptic seizures.

WHO To prevent seizure in a woman with severe pre-eclampsia.

Prevention and treatment of eclampsia.

SOGC Eclampsia.

Women with severe pre-eclampsia to prevent eclampsia (prophylaxis).

Consider for women with non-severe pre-eclampsia.


Table H.2 Recommended intravenous (IV) loading dose of magnesium sulphate for treating pre-eclampsia and eclampsia

Guidelines Condition (see Table H.1 for details)

Dosage in Grams (g)

Infusion by infusion pump Infusion by syringe pump Other

Volume MgSO4 Solution concentration

Time Volume

MgSO4 Solution concentration

Time

NSW Pre-eclampsia/ Eclampsia

4 g 108 mL add 8 mL of 50% soln to 100 mL saline

20-30 min 8 mL 9 mL of 50% soln, prime line with 1 mL

15 min

The Royal Women’s Hosp, VIC

Pre-eclampsia 4 g 8 mL 50% soln 15 min

Eclampsia 4 g 8 mL 50% soln 5 min to 10 min

SA Pre-eclampsia 4 g 20 mL 40 mL 50% soln in 60 mL saline

20 min 8 mL 50% soln 20 min

Eclampsia 4 g 20 mL 40 mL 50% soln in 60 mL saline

10 min 8 mL 50% soln 10 min

RCOG Eclampsia 4 g 5-10 min IV by infusion pump

SOMANZ Eclampsia 4 g 10-15 min IV infusion (no details of type)

WHO Pre-eclampsia/ 4 g IV infusion (20% solution) over 5 min

Eclampsia

If blank then this indicates no information for this variable

If separate regimens were given for the different conditions then these are stated, if not stated separately, only one regimen was given for both conditions.

soln=solution

SCOG gives no recommendations on volume or concentration


Table H.3 Recommended intravenous (IV)* maintenance dose of magnesium sulphate for the treatment of pre-eclampsia and eclampsia

Guideline Condition (see Table H.1 for details)

Dosage in grams (g)

Timing Infusion by infusion pump Infusion by syringe pump Other Time period for continuing maintenance dose

Volume Per hour


Volume Per hour


NSW Pre-eclampsia / Eclampsia

1 g per hour

40 mL add 20 mL of MgSO4 50% soln to 380 mL saline

2 mL 50 mL of 50% soln, prime line with 1 mL

At least 24 hrs


Pre-eclampsia / Eclampsia

1 g per hour

2 mL 50 mL of 50% soln

At least 24 hrs after birth

SA Pre-eclampsia / Eclampsia

1 g per hour

5 mL 20% soln (40 mL 50% soln in 60 mL saline)

2 mL 50% soln For 24 hrs after last seizure and 24 hr after birth

RCOG Eclampsia 1 g per hour

Later of 24 hrs after last seizure or 24 hrs after birth Unless clinical reason for continuing

SOMANZ Eclampsia 1-2 g per hour

IV infusion (no details of type)

For 24 hrs after last seizure

SCOG gives no recommendations on volume or concentration

*WHO recommends intramuscular maintenance



Table H.4 Recommended prenatal maternal monitoring during loading dose (if separately documented): indications for stopping treatment and time interval

between monitoring with magnesium sulphate for pre-eclampsia and eclampsia

Guideline Maternal blood Pressure

Respiratory Rate

Pulse Urine output

Patellar reflexes Serum MgSO4

Serum Creatinine

Other

NSW Check after completion of loading dose

Close observation and assessment required for duration of infusion.


5min (x4 readings) 5min (x4 readings) Check after completion of loading dose

Observe for development of side effects

SOGC, WHO, SOMANZ, RCOG and SA do not give any separate recommendations for maternal monitoring during treatment


Table H.5 Recommended prenatal maternal monitoring during maintenance dosage: time interval between monitoring and indications for review or stopping

treatment with magnesium sulphate for pre-eclampsia and eclampsia

Guideline Maternal blood Pressure

Respiratory Rate

Pulse Urine output Serum creatinine

Patellar reflexes

Serum MgSO4 Other

NSW 1-2 hr 1-2 hr, stop if <10 breaths per min

1-2 hr 1-2 hr, Stop if <30 mL for 3 consecutive hrs

2 hrs, Stop if absent

At 1 hr after commencing infusion then as clinically indicated

Where woman’s condition is unstable increase frequency of observation


0.5 hr 0.5 hr should be ≥16 per min, review if <12 per min

0.5 hr 1 hr urine, 4 hrs urinary protein Review if <100 mL urine in 4 hrs

1 hr, Review if absent

6 hrs or Request if any of respiratory, urine or reflexes are under review or further seizures or renal impairment.

2 hr temperature **ECG monitoring and anaesthetist aware of woman’s medical condition

SA 1hr 1 hr, stop if <10-12 breaths per min

insert indwelling catheter and monitor 1hrly, if <100 ml over 4 hrs check serum MgSO4

6 hrs, if >100mmol/L check serum MgSO4

Minimum 4 hourly, stop if absent

Test 6 hrly if serum creatinine >100 mmol/L or urine <100 mL over 4 hrs

1hr Pulse SpO2 oximeter **ECG monitoring and anaesthetist on site

SOMANZ YES YES YES YES YES Oxygen saturation

RCOG If respiratory rate depression (no details) give calcium gluconate 1 g over 10 min

Stop if <20 mL/hr Stop if absent

“Magnesium toxicity is unlikely with these regimens and levels do not need to be routinely measured”

WHO Stop or delay if <16 per min

Stop or delay if output is less than 30 mL per hr over preceding 4 hrs

Stop or delay if absent

** for eclamptic seizures only


Table H.6 Antidote for magnesium sulphate toxicity

Guidelines Antidote

NSW Calcium chloride or calcium gluconate (10 mL of 10% solution) by slow intravenous injection over 3 minutes.

The Royal Women’s Hosp, VIC Calcium gluconate (10 mL of 10% solution over 10 minutes) by slow intravenous injection. The patient requires ECG monitoring during and after administration because of the potential for cardiac arrhythmias. Resuscitation and ventilator support should be available during and after administration of both magnesium sulphate and calcium gluconate.

SA Call for medical assistance, administer oxygen at 8-12 litres, stop infusion, monitor vital signs. Administer Calcium gluconate (10% solution), 10 mL, slowly, IV check electrolytes, creatinine, magnesium sulphate concentrations.

RCOG Calcium gluconate 1 g (10 mL) over 10min can be given if concern over respiratory depression.

WHO Give calcium gluconate 1 g (10 mL of 10% soln) IV slowly over 10 min until respirations satisfactory. Assist ventilation using mask and bag, anaesthetic apparatus or intubation.

SOMANZ and SOGC do not give recommendations of antidote

Table H.7 Details of magnesium sulphate concentrations and effects (taken from The Royal Women’s Hospital, VIC guidelines)

Magnesium sulphate concentrations (mmol/L)

Effects

0.8-1.0 Normal plasma concentrations

1.7-3.5 Therapeutic range

2.5-5.0 ECG changes (P-Q interval prolongation, widen QRS complex)

4.0-5.0 Reduction in deep tendon reflexes

>5.0 Loss of deep tendon reflexes

>7.5 Sinoatrial and atrioventricular blockade. Respiratory paralysis and CNS depression

>12 Cardiac arrest


References

Guidelines for the management of hypertensive disorders of pregnancy 2008. Society of Obstetric Medicine of Australia and New Zealand (SOMANZ).

The management of severe preeclampsia/eclampsia. Royal College of Obstetricians and Gynaecologists (RCOG) Guideline No. 10(A). March 2006.

Clinical practice guidelines: Diagnosis, evaluation and management of hypertensive disorders of pregnancy. The Society of Obstetricians and Gynaecologists of Canada

(SOGC). Journal of Obstetrics and Gynaecology Canada volume 30 March 2008 supplement 1.

Magnesium sulphate protocol CPG. Magnesium sulphate is the anticonvulsant of choice for preeclampsia prophylaxis and treatment. The Royal Women’s Hospital,

Victoria, Australia. Dec 2009.

Policy directive. Magnesium sulphate (MgSO4) infusion protocol for eclamptic seizure prophylaxis. New South Wales Department of Health, Australia.

Education material for teachers of midwifery. Midwifery education modules -2nd edition. Managing eclampsia. World Health Organization (WHO).

Maternity care in South Australia. Perinatal practice guidelines. Section 6 chapter 96. Magnesium sulphate infusion regimen. 26th Oct 2009.


Recommended loading dose of magnesium sulphate from trials

Trial Arm of trial Dosage in

Grams (g)

Infusion Other details

Volume MgSO4 solution concentration time type

Rouse 2008 6 g 20-30 min IV infusion

Crowther 2003 4 g 8 mL 16 mmol of 0.5% MgSO4 soln 20 min IV infusion

Marret 2006 4 g 40 mL 0.1g/mL MgSO4 soln 30 min IV infusion Single dose

Mittendorf 2002 Tocolytic 4 g IV infusion

Neuroprotective 4 g Single dose


Recommended maintenance dose of magnesium sulphate from trials

Trial Arm of trial Dosage in

Grams (g)

Infusion Other details

Volume MgSO4 solution concentration time type

Rouse 2008 2 g Per hr IV infusion

Crowther 2003 1 g 2 mL 0.5% MgSO4 soln Per hr IV infusion

Marret 2006 No maintenance dose given

Mittendorf 2002 Tocolytic 2-3 g Per hr IV infusion

Neuroprotective No maintenance dose given



Recommended prenatal maternal monitoring during magnesium sulphate dosage for fetal, infant and child neuroprotection

Trial Monitoring Cease treatment

Rouse 2008 No details Discontinue if birth had not occurred after 12 hrs and no longer considered imminent

Crowther 2003 Pulse rate, blood pressure, respiratory rate monitored throughout infusion and any maternal adverse events recorded

Stop if respiratory rate decreases more than 4/min below baseline, diastolic blood pressure decreases more than 15mmHg below baseline

Marret 2006 Pulse rate, blood pressure, respiratory rate, tendon reflex and any maternal adverse effects recorded throughout infusion

Stopped at anaesthetist discretion

Mittendorf 2002 Pulse rate, blood pressure/respiratory rate monitored throughout infusion and maternal side effects recorded

Stop if respiratory rate drops below 16/min or if blood pressure drops more than 15mm Hg below baseline


Appendix I: Public consultation comments and Panel responses

Comment Received Response/Justification

1 Patient information sheets

Information sheets and/or leaflets be designed

and provided which will provide clear and

comprehensive information and explanation of

the treatment and range of side effects so that

women are able to make an informed decision.

Information sheets relevant for consumers will be

prepared and disseminated after the main

guideline documents have been finalised.

2 Information and education for midwives.

A comprehensive strategy be considered to

ensure that midwives can access information and

education regarding the administration of

magnesium sulphate during the antenatal period

for women at high risk of pre term labour.

The clinical practice guidelines provide guidance on

administration of magnesium sulphate during the

antenatal period and will be readily available for

use by midwives in their practice. In addition we

expect that individual centres will already have

individual obstetric unit protocols or develop more

detailed local protocols based on the Guidelines.

3 Patient care during administration of

magnesium sulphate.

During administration of magnesium sulphate the

woman should receive one on one midwifery

care in the birthing suite of a facility (not in an

antenatal or postnatal ward).

When magnesium sulphate is administered the

recommended monitoring under good practice

points should be available. We expect that each

maternity health facility will have their own

protocols regarding models of care.

4 Audit and follow up.

Long term audit and follow up of the women and

babies who have received magnesium sulphate

prior to 30 weeks’ gestation to ensure benefit.

Agree. The Guidelines recommend an audit

process (page 14).

5 Further research.

Further research is prioritised to studying the

impact for women of administration of

magnesium sulphate.

Agree. The priority research recommendations are

given within the guidelines (page 14) and these

focus on outcomes for women and their babies.

6 Monitoring recommendations.

Minimum standards of observations to include:

a. monitoring of oxygen saturation;

a. The Panel consider that monitoring oxygen saturation is not required as a minimum standard – respiratory rate is reduced by magnesium sulphate serum concentrations above the therapeutic range and therefore is an appropriate minimum observation for respiratory depression. Recording respiratory rate has been a standard monitoring requirement for using magnesium sulphate for


b. reflexes prior to loading dose to gain

baseline reflex responses; c. temperature; and

d. continuous fetal heart monitoring

pre-eclampsia. b. This has been added to baseline assessment

within the Guidelines. c. The flushing experienced by women with a

magnesium sulphate infusion is not related to a temperature rise. Routine temperature monitoring is therefore not required.

d. The method and frequency of monitoring the fetal heart should be determined by the underlying clinical condition of the woman and her fetus.

7 Gestation at which magnesium sulphate is administered.

Evidence supports a likely benefit in the large group of infants born between 30.0 and 33.6 weeks’ gestation. We would consider 32 weeks’ gestation as a compromise position.

The Panel decided that current evidence to support this wider interpretation is not strong enough for National Clinical Guidelines therefore the recommendations are not open to all gestational ages at this point in time. Further research of higher gestational ages through RCTs and individual patient data (IPD) meta-analysis is needed and in planning stages.

8 Timing of magnesium sulphate administration.

The clinical recommendation and relevant good practices points should be combined to achieve greater clarity and consistency.

The clinical recommendation and good practice points each deal with a different clinical scenario; time to give magnesium sulphate prior to planned birth time; severe fetal and maternal compromise; and birth expected within 4 hours. The Panel considered that the clinical recommendation should stand alone and be supported by separate good practice points.

9 Loading dose regimen for magnesium sulphate.

Clinical recommendation is confusing.

The Panel consider that a statement about no immediate repeat doses is important and appropriate to include within the clinical recommendation.

10 Repeat magnesium sulphate at a later gestation if birth does not occur when magnesium sulphate first administered.

Giving discretion to the ‘attending health professional’.

As evidence about need for repeat doses is presently unclear no firm recommendation can be given. The decision needs to be at the discretion of the attending health professional.

11 Nifedipine administration.

The interaction between magnesium sulphate and nifedipine in relation to hypotension.

We have included additional information about hypotension in monitoring under good practice points.

Antenatal Magnesium SulphatePrior to Preterm Birth for Neuroprotection

of the Fetus, Infant and Child

Antenatal M

agnesium Sulphate Prior to Preterm

Birth for Neuroprotection of the Fetus, Infant and Child

Prepared by the

Antenatal Magnesium Sulphate

For Neuroprotection

Guideline Development Panel

2010

Nati onal Clinical Practi ce Guidelines

2010 - University of Auckland

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Transcript of 2010 - University of Auckland